Identification of dysregulated genes in patients with multiple sclerosis

Abstract

The present invention identifies a number of gene markers whose expression is altered in multiple sclerosis (MS). These markers can be used to diagnose or predict MS in subjects, and can be used in the monitoring of therapies. In addition, these genes identify therapeutic targets, the modification of which may prevent MS development or progression.

Description

BACKGROUND OF THE INVENTION

[0001] The present application claims benefit of priority to U.S. Provisional Serial No. 60/379,284, filed May 9, 2003, the entire contents of which are hereby incorporated by reference.

[0002] 1. Field of the Invention

[0003] The present invention relates generally to the fields of molecular biology, genomics, immunology and neurobiology. More particularly, it concerns the identification of specific genes that are dysregulated in patients afflicted with multiple sclerosis (MS). These genes can be used to identify subjects suffering from or at risk of MS, and can also provide targets for MS therapies.

[0004] 2. Description of Related Art

[0005] Multiple sclerosis (MS) continues to be a serious health problem that afflicts hundreds of thousands each year in the US alone, and millions worldwide. One of the difficult aspects of dealing with MS is identifying patients early in the course of the disease. This is difficult not only because of the lack of a definitive biological test for MS, but because the symptoms may overlap with those of numerous other diseases.

[0006] The concordance rate of multiple sclerosis among monozygotic twins is 20-40%, while the risk of a non-twin sibling of an MS patient of developing MS is 2-4%. These facts highly suggest the presence of polygenic susceptibility (nonmendelian inheritance). Although no single gene is associated with all types of MS, several reports have revealed that some genes are associated with MS in certain populations. The well known HLA association with MS has been demonstrated in populations of northern European ancestry. In the Finnish population an association with the myclin basic protein gene has been reported (Tienari et al., 1992). In an European MS patient population, an association with a T cell differentiation-related antigen, CD45, has been demonstrated (Jacobsen et al., 2000).

[0007] Since the disease is polymorphic (i.e., not inherited in a classical mendelian pattern but clearly multiple genes are involved in leading to predisposition), recent genomic approaches have been implemented to elucidate multiple genes simultaneously that may be associated with the disease. A recent publication by Lock et al., 2002, demonstrates how gene expression profiling using DNA microarrays to examine MS brain tissues can help identify multiple single genes that are associated with the disease, and may therefore serve as targets of treatment. By altering the function of the product of some of these genes in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), these authors confirmed that some genes found to be altered by DNA microarray screening indeed had an impact on the severity of the disease.

[0008] Another approach to identify potential single gene associations is to examine polymorphic gene variants or single nucleotide polymorphisms (SNPs) of candidate genes, or screen the entire genome to establish the SNPs that are associated with the disease. Multiple polymorphisms have been associated with MS, as follows: a) polymorphisms associated with MS disease susceptibility found in the following genes: SCA2 (Chataway et al., 1999), interferon α (Miterski et al., 1999), estrogen receptor (Niino et al., 2000), plasminogen activator inhibitor 1 (Luomala et al., 2000), tumor necrosis factor a (Femandez-Arquero et al., 1999; Lucotte et al., 2000), monocyte chemotactic protein 3 (Fiten et al., 1999), vitamin D receptor (Fukazawa et al., 1999), CTLA4 (Fukazawa et al., 1999), γ aminobutyric acid (Gade-Andavolu et al., 1998); b) polymorphisms associated with disease severity found in the following genes: interleukin 6 (Vandenbroeck et al., 2000), IgG Fe receptor (FCγ R) (Myhr et al., 1999), glutathione-S-transferase (Mann et al., 2000); c) polymorphisms associated with age of onset of MS found in the following genes: interleukin 4 (Vandenbroeck et al., 1997) and chemokine receptor CCR5 (Barcellos et al., 2000); and d) polymorphism associated with remyclination capacity: apolipoprotein E (Carlin et al., 2000). Other gene polymorphisms that have been associated with MS include intercellular adhesion molecule 1 (ICAM-1) (Mycko et al., 1998), the pro-inflammatory gene lymphotoxin (Mycko et al., 1998) and immunoglobulin heavy chain gene polymorphisms (Hashimoto et al., 1993; Walter et al., 1991).

[0009] Despite these individual associations, there has yet to be put forth a cohesive set of genes that, as a group, provide accurate diagnostic or prognostic information regarding MS. Thus, there remains a need for a genetic based test that identifies individuals having or at risk of developing MS.

SUMMARY OF THE INVENTION

[0010] Thus, in accordance with the present invention, there is provided a method of predicting whether a subject is or will be afflicted with multiple sclerosis (MS) comprising (a) obtaining an mRNA-containing sample from said subject; (b) determining expression information for one or more genes from the set of highest discriminatory genes selected from the group consisting of phosphatidylinositol transfer protein, inducible nitric oxide synthase, CIC-1 (CLCN1) muscle chloride channel protein, placental bikunin (AMBP), receptor kinase ligand LERK-3/Ephrin-A3, GATA-4, thymopoietin, transcription factor E2f-2, S-adenosylmethionine synthetase, carcinoembryonic antigen, ret transforming gene, G protein-linked receptor (clone GPCR W), GTP-binding protein RALB, tyrosine kinase Syk, T cell leukemia LERK-2/Ephrin-B1, tyrosine kinase (ELK1) oncogene, transcription factor SL1, phospholipase c, gastricsin (progastricsin), and D13S824E locus; (c) comparing expression information for said selected genes with the expression information of the same genes in a subject not afflicted with MS; and (d) predicting whether said subject is or will be afflicted with MS. The sample may comprise peripheral blood-derived mononuclear cells. The method may further comprise determining expression information for one or more genes in Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. The method may also further comprise obtaining expression information for each gene in step (b), or for one or more genes in Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, from a subject not afflicted with MS. The expression information for more than one gene in the group above may be determined, such as expression information for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes.

[0011] Expression information may be determined by microarray analysis of mRNA transcripts, by northern blots, RNAse protection assays, and multiplex or real-time PCR of mRNA transcripts, or by immunohistochemistry, ELISA or western analysis. Microarray analysis may comprise use of oligonucleotides that hybridize to mRNA transcripts or cDNAs for the selected genes, and the oligonucleotides may be disposed or directly synthesized on the surface of a chip or wafer. The oligonucleotides may be about 10 to about 50 base pairs in length.

[0012] In another embodiment, there is provided a chip or wafer comprising a nucleic acid microarray, wherein said nucleic acids hybridize to target transcripts or cDNAs for phosphatidylinositol transfer protein, inducible nitric oxide synthase, CIC-1 (CLCN1) muscle chloride channel protein, placental bikunin (AMBP), receptor kinase ligand LERK-3/Ephrin-A3, GATA-4, thymopoietin, transcription factor E2f-2, S-adenosylmethionine synthetase, carcinoembryonic antigen, ret transforming gene, G protein-linked receptor (clone GPCR W), GTP-binding protein RALB, tyrosine kinase Syk, T cell leukemia LERK-2/Ephrin-B1, tyrosine kinase (ELK1) oncogene, transcription factor SL1, phospholipase c, gastricsin (progastricsin), and D13S824E locus. The chip may be comprised of polymers, plastics, resins, polysaccharides, silica or silica-based materials, fiberoptic materials, carbon, metals, inorganic glasses, or nitrocellulose. The nucleic acids may be partial or full length cDNAs, or oligonucleotides of about 10 to about 50 base pairs or less in length.

[0013] In yet another embodiment, there is provided a method for monitoring a therapy for multiple sclerosis comprising (a) obtaining an mRNA-containing sample from a subject receiving said therapy; (b) determining expression information for one or more genes comprising phosphatidylinositol transfer protein, inducible nitric oxide synthase, CIC-1 (CLCN1) muscle chloride channel protein, placental bikunin (AMBP), receptor kinase ligand LERK-3/Ephrin-A3, GATA-4, thymopoietin, and transcription factor E2f-2, S-adenosylmethionine synthetase, carcinoembryonic antigen, ret transforming gene, G protein-linked receptor (clone GPCR W), GTP-binding protein RALB, tyrosine kinase Syk, T cell leukemia LERK-2/Ephrin-B1, tyrosine kinase (ELK1) oncogene, transcription factor SL1, phospholipase c, gastricsin (progastricsin), and D13S824E locus; and (c) comparing expression information for said selected genes with the expression information of the same genes in an MS subject not receiving said therapy. The sample may be peripheral blood. The method may further comprise modifying said therapy based upon the altered expression of one or more of said selected genes. The method may further comprise making a prediction on the efficacy of treating the subject from which said sample was obtained. The expression information may be determined by microarray analysis of mRNA transcripts, by northern blots, RNAse protection assays, and multiplex or real-time PCR of mRNA transcripts, or by immunohistochemistry, ELISA or western analysis.

[0014] The microarray analysis may comprise use of oligonucleotides that hybridize to transcripts or cDNAs for the selected genes, and wherein the oligonucleotides are disposed or synthesized directly on the surface of a chip or wafer. The chip may be comprised of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose. The oligonucleotides may be about 10 to about 50 base pairs or less in length. The MS subject not receiving said therapy may be the same subject prior to receiving said therapy. The method may further comprise determining expression information for said selected genes from said subject at multiple time points.

[0015] In still yet another embodiment, there is provided a method for determining the efficacy of a therapy for multiple sclerosis comprising (a) obtaining an mRNA-containing sample from a subject receiving said therapy; (b) determining expression information for one or more selected genes selected from the group consisting of skeletal muscle LIM-protein SLIM1 (also known as four and a half LIM domains 1 (FHL1)), R kappa B, 815A9.1 myosin heavy chain (MYH11), γ G2 psi from γ crystallin, thrombospondin 4 and KIAA0178 (OR Z97054); (c) comparing expression information for said one or more selected genes with the expression information of the same gene or genes in an MS subject not receiving said therapy; and (d) determining the efficacy of said therapy based on the ability of said therapy to alter the expression of said one or more genes. The method may further comprise determining expression information for one or more genes in Table 14 or Table 15.

[0016] In a further embodiment, there is provided a method for treating multiple sclerosis (MS) comprising administering to a subject with MS a drug that causes an increase in the level of a gene product selected from the group consisting of those genes indicated by a minus (−) sign in Tables 1-12. In still yet a further embodiment, there is provided a method for treating multiple sclerosis (MS) comprising administering to a subject with MS a drug that causes a decrease in the level of a gene product selected from the group consisting of those genes indicated by a plus (+) sign in Tables 1-12 and 16.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0018] FIG. 1—Estimation of false positive error based on H0 and H1 distributions.

[0019] FIG. 2—FDA projections of peripheral blood samples from four classes. ALS=amyotrophic lateral sclerosis; Healthy=healthy donor; MS=multiple sclerosis; MSA=multiple sclerosis patients on Avonex.

[0020] FIG. 3—Eight preferred genes used to determine whether a given blood sample originated from an MS patient. MS vs. ALS and healthy donors were compared using 7 MS (a heterogeneous population), 8 ALS, and 7 healthy donor samples. This list was then compared to the lists from Tables 7-9, in which only 5 samples are included in each group (the 5 MS samples in Tables 7-9 are homogeneous, all with classical relapsing-remitting MS on no treatment). Eight genes were selected based on false positive error probability (only discriminatory genes whose false positive errors are less than 0.001 and are shared in these lists are selected). Autoscaled expressions were calculated by standardizing each gene's expression into zero mean and unit variance (variance=1).

[0021] FIGS. 4A-D—In vitro and in vivo validation of MS PBMC targets. FIG. 4A. Quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) fold change results of selected genes, including the E2F1 transcription-dependent E2F2 and the myelin gene MOBP, in a set of MS PBMC-derived RNAs unrelated to those used for microarray analysis, as compared to healthy donors. FIG. 4B. Demonstration that E2f1 deficient mice (&Circlesolid;) have lower disability scores (less disabling form of the disease) during myelin oligodendrocyte glycoprotein (MOG)-induced EAE (P<0.05 by Fisher's protected least significant difference (PLSD) test in days denoted by thick lines under the graph) as compared to wild type (WT) EAE mice (□) and C57BL/6 EAE mice (▴) (n=7 each group); the day of disease onset was not significantly altered. FIG. 4C. Propidium iodide-fluorescence activated cell sorter (PI-FACS) cell cycle analysis of splenocytes isolated from all E2f1 deficient (gray bars), WT EAE (black bars) and C57BL/6 (white bars) mice in the study. Splenocytes from E2f1 deficient mice with EAE exhibit decreased entry into S phase, as compared to splenocytes from WT EAE mice (* P<0.05 by Fisher's PLSD).

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0022] In autoimmune diseases, activated T cells, B cells and monocytes are hypothesized to clonally expand (i.e., proliferate into multiple daughter cells) and lead to tissue destruction, via infiltration of target tissues with direct cytotoxicity and/or release of harming soluble factors or antibodies. MS is widely considered an autoimmune disease, but there is significant controversy about the key molecules that participate in such process. Further, it is known that various autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and MS, do not share all aspects of autoimmunity at the molecular level. This makes sense since it is believed that these different mechanisms are responsible for the target tissue specificity, the difference in biomarkers required to confirm the diagnosis, and the different types of lesions seen.

[0023] Therefore, the inventors used DNA microarrays to identify the gene signature of peripheral blood mononuclear cells in multiple sclerosis, revealing multiple new genes that have not been previously considered as biomarkers for this disease. In a comparison of healthy donors to either MS (an autoimmune disease) or ALS (not autoimmune), massive changes were found in gene expression, as would be expected, only in MS peripheral blood. Thus, the inventors have used ALS as a negative disease control to dissect out the autoimmune disease-related biomarkers. In addition, the inventors encountered gene expression abnormalities on a series of pathways, some of which have been previously implicated in autoimmunity, leading further credence to the accuracy of their method in establishing novel and specific biomarkers.

[0024] I. Multiple Sclerosis

[0025] Multiple Sclerosis (MS) is one of the most common diseases of the central nervous system (brain and spinal cord). It is an inflammatory condition caused by demyelination, or loss of the myelin sheath. Myelin, a fatty material that insulates nerves, acts as insulator in allowing nerves to transmit impulses from one point to another. In MS, the loss of myelin is accompanied by a disruption in the ability of the nerves to conduct electrical impulses to and from the brain and this produces the various symptoms of MS, such as impairments in vision, muscle coordination, strength, sensation, speech and swallowing, bladder control, sexuality and cognitive function. The plaques or lesions where myelin is lost appear as hardened, scar-like areas. These scars appear at different times and in different areas of the brain and spinal cord, hence the term “multiple” sclerosis, literally meaning many scars.

[0026] Currently, there is no single laboratory test, symptom, or physical finding that provides a conclusive diagnosis of MS. To complicate matters, symptoms of MS can easily be confused with a wide variety of other diseases such as acute disseminated encephalomyclitis, Lyme disease, HIV-associated myelopathy, HTLV-1-associated myelopathy, neurosyphilis, progressive multifocal leukoencephalopathy, systemic lupus erythematosus, polyarteritis nodosa, Sjögren's syndrome, Behcet's disease, sarcoidosis, paraneoplastic syndromes, subacute combined degeneration of cord, subacute myelo-optic neuropathy, adrenomyeloneuropathy, spinocerebellar syndromes, hereditary spastic paraparesis/primary lateral sclerosis, strokes, tumors, arterioyenous malformations, arachnoid cysts, Amold-Chiari malformations, and cervical spondylosis. Consequently, the diagnosis of MS must be made by a process that demonstrates findings that are consistent with MS, and also rules out other causes.

[0027] Generally, the diagnosis of MS relies on two criteria. First, there must have been two attacks at least one month apart. An attack, also known as an exacerbation, flare, or relapse, is a sudden appearance of or worsening of an MS symptom or symptoms which lasts at least 24 hours. Second, there must be more than one anatomical area of damage to central nervous system myclin sheath. Damage to sheath must have occurred at more than one point in time and not have been caused by any other disease that can cause demyelination or similar neurologic symptoms. MRI (magnetic resonance imaging) currently is the preferred method of imaging the brain to detect the presence of plaques or scarring caused by MS.

[0028] The diagnosis of MS cannot be made, however, solely on the basis of MRI. Other diseases can cause comparable lesions in the brain that resemble those caused by MS. Furthermore, the appearance of brain lesions by MRI can be quite heterogeneous in different patients, even resembling brain or spinal cord tumors in some. In addition, a normal MRI scan does not rule out a diagnosis of MS, as a small number of patients with confirmed MS do not show any lesions in the brain on MRI. These individuals often have spinal cord lesions or lesions which cannot be detected by MRI. As a result, it is critical that a thorough clinical exam also include a patient history and functional testing. This should cover mental, emotional, and language functions, movement and coordination, vision, balance, and the functions of the five senses. Sex, birthplace, family history, and age of the person when symptoms first began are also important considerations. Other tests, including evoked potentials (electrical diagnostic studies), cerebrospinal fluid, and blood (to rule out other causes), may be required in certain cases. Currently, there are no genetic markers that permit the diagnosis of MS. To date, the best association in large population studies with the risk of having MS is found in genomic screens within the HLA (chromosome 6) region, but it is clear that this association, albeit germane to a relative genetic predisposition, is insufficient even to suggest a diagnosis.

[0029] II. MS-Related Genes

[0030] In the following pages, applicants set forth those gene targets that may be used to diagnose/prognose MS based upon the relevant comparison. Also included are the particular probes utilized.

[0031] In the following tables, a plus (+) sign next to a probe set or gene name indicates higher expression observed in patients with MS (Tables 1-12, and 16), highlighting its diagnostic or prognostic value for MS, or it signifies that the gene or probe set is downregulated in MS patients that are receiving Avonex (the latter only applies to Tables 13-15). For example, thrombospondin 4 (+) (Table 13) indicates that this gene is higher in MS patients that in MS patients receiving Avonex. It suggests that Avonex may downregulate this inflammation-related gene and therefore thrombospondin 4 could be a target molecule to devise therapies for MS. Similarly, E2F-3 (+) (Table 15) means that this pro-proliferative transcription factor for immune cells is downregulated by Avonex, suggesting that manipulating the E2F pathway may have beneficial effects in MS.

[0032] The numbers under “Probe sets” represent the GenBank accession numbers or, in some instances, an identifier provided by Affymetrix.

TABLE 1
Highly discriminatory genes for MS (on no treatment) vs. Healthy Donors
Probe sets	Gene Descriptions	Up (+) or Down (−)
D30037	phosphatidylinositol transfer protein (PITPN)	+
D29675	Inducible nitric oxide synthase (iNOS)	+
U78095	Placental bikunin (AMBP)	+
U18271	thymopoietin (TMPO)	+
D64158	cell differentiation-associated ATP binding protein	+
Z25884	CIC-1 muscle chloride channel protein (CLCN1)	+
U14187	receptor tyrosine kinase ligand LERK-3/Ephrin-A3	+
Z16411	phospholipase c; Also: U26425, Z37544 (PLCB3)	−
U79528	SR31747 binding prot 1 (SRBP1); Also: U75283	+
X72879	14A2AK DNA sequence	+
L34357	GATA4	+
M76424	carbonic anhydrase VII (CA VII)	+
M25269	tyrosine kinase (ELK1)	+
HG2415-	Transcription Factor E2F2	+
HT2511
Z49254	L23-related MRPL23	−
HG3175-	Carcinoembryonic Antigen	+
HT3352
Z78289	(clone 1D2)/Z78289	+
Z15114	protein kinase C gamma (PRKCG)	+
AC002486	BAC clone RG367O17/7p15-p21/AC002486	+
HG3991-	Cpg-Enriched Dna, Clone E18	+
HT4261
D26069	Centaurin beta 2 (CENTB2)/KIAA0041	+
U25975	serine kinase (hPAK65)	+
D87450	parallel sister chromatids drosophila protein-like/KIAA0261	+
S68874	EP3 prostanoid receptor EP3-I	+
D45132	kidney zinc-finger DNA-binding protein PRDM2	+
Y09443	alkyl-dihydroxyacetonephosphate synthase AGPS	+
M13994	BCL2-alpha; Also: M14745	+
X60483	H4/D histone	+
M98833	ERGB TRANSCRIPTION FACTORS (FLI-1 homolog)	+
U79303	clone 23882	+
Z47038	putative microtubule-associated; protein 1A (MAP1A)	+
HG3638-	Amyloid Beta (A4) Precursor prot; Also: Y00264	−
HT3849
U03398	receptor 4-1BB ligand (TNFSF9)	+
U66059	TCRBV1S1A1N1 from germline T-cell receptor beta chain	+
HG2825-	Ret Transforming	+
HT2949
L36922	Met-ase 1/Granzyme M (GZMM)	+
U39318	E2 ubiquitin conjugating enzyme UbcH5C (UBCH5C)	+
U49837	LIM prot MLP (CSRP3)	+
U31903	CREB-RP (CREBL1); Also: U89337_1, X98054	+
X80878	R kappa B (NFRKB)	+
D30036	phosphatidylinositol transfer protein (PITPN)	+
S76992	VAV2	+
D83779	Hypothetical protein/KIAA0195	+
D26579	transmembrane prot ADAM8	+
X90857	(−14) containing globin regulatory element (CGTHBA)	−
X13444	CD8 beta-chain glycoprot (CD8 beta1)	+
M30818	interferon-induced cellular resistance mediator MxB (MX2)	+
M19650	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
HG4108-	Olfactory Receptor Or17-24	+
HT4378
X89067	trpc2 transcript	+
X83492	Fas/APO1 (TNFRSF6)	+
L19593	IL-8 receptor beta (IL8RB)	+
D49490	disulfide isomerase-related protein (PDIR)	+
X89267	DNA uroporphyrinogen decarboxylase (UROD)	+
D16217	Calpastatin (CAST)	+
L05512	histatin 1 (HTN1)	+
D38024	facioscapulohumeral muscular dystrophy (FSHD)	+
U79262	Deoxyhypusine	+
D38491	Hypothetical protein/KIAA0117	+
M28879	granzyme B/CTLA-1 (GZMB)	+
Y10936	hypothetical protein downstream of DMPK and DMAHP	+
Y09022	Not56-like protein (NOT56L)	+
L35253	p38 mitogen activated prot (MAP) kinase; Also: L35264	+
HG644-	Histone H1.1 (HIST1H1A)	−
HT644
S50017	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
X75755	PR264; Also: HG3088-HT3261	+
M29971	6-O-methylguanine-DNA methyltransferase (MGMT)	−
X07619	cytochrome P450 db1 variant b; Also: X16866	+
U53347	neutral amino acid transporter B (SLC1A5)	+
M21259	Alu repeats in the region to the Snrp E	−
S82597	UDP-GaINAc: N-acetylgalactosaminyltransferase GALNT1	+
U78521	immunophilin homolog ARA9	+
U47635	D13S824E locus	−
D28364	annexin II (ANXA2)	+
U59752	Sec7p-like protein (PSCD2L)	+
Z19585	thrombospondin-4 (THBS4)	+
Y00282	ribophorin II (RPN2)	−
U43431	DNA topoisomerase III alpha (TOP3A)	−
U63541	expressed in HC/HCC livers and MoIT-4 proliferating cells	+
S81957	bone morphogenic protein 5 (BMP5)	+
D38550	E2F3 transcription factor/KIAA0075	+
D38449	G protein-coupled receptor (GPR)	+
D38524	5-nucleotidase (NT5C2)	+
HG4114-	Olfactory Receptor Or17-209	+
HT4384
D86979	hypothetical protein/KIAA0226	+
U57341	neurofilament L (NFL)	+
D49487	obese/Leptin (LEP); Also: U43653	+
D86043	SHPS-1/PTPNS1 tyrosine phosphatase; Also: U06701	−
L76200	guanylate kinase (GUK1)	−
U20647	zinc finger protein (ZNF151)	+

[0033]

TABLE 2
Intermediate discriminatory genes for MS
(on no treatment) vs. Healthy Donors
L34075	FKBP-rapamycin associated prot (FRAP)	+
U07807	metallothionein IV (MTIV)	+
X65977	corticostatin HP-4 precursor (defensin/DEFA4)	+
X05309	C3b/C4b receptor (CR1) F allotype.	+
D87076	Br140/KIAA0239	+
D42046	DNA replication helicase-like homolog/KIAA0083	+
U15173	Nip2 (NIP2)	+
U07550	Chaperonin 10 (HSPE1)	−
HG2479-	Helix-Loop-Helix prot Sef2-1D; Also: M74719	+
HT2575
HG4094-	Transcription Factor LSF-Id; Also: U03494	+
HT4364
X16316	VAV1	+
U41068	retinoid X receptor beta (RXRbeta) 3	+
U43030	cardiotrophin-1 (CTF1)	+
D82344	NBPhox (PHOX2B)	+
U34301	Nonmuscle myosin heavy chain IIB	+
HG3730-	Tyrosine Kinase Syk; Also: L28824	+
HT4000
M20778	alpha-3 (VI) collagen; Also: X52022	+
AB001325	Aquaporin 3 (AQP3)	+
D28114	myelin-associated oligodendrocytic basic protein	+
	(MOBP)
U52154	G-coupled inwardly rectifying potassium channel KIR34	+
X79865	Mrp17/Mitochondrial ribosomal L12 (MRPL12)	−
U76388	steroidogenic factor 1 (NR5A1)	+
D31883	actin-binding LIM protein 1 (ABLIM1)/KIAA0059	+
Z14244	coxVIIb cytochrome c oxidase subunit VIIb (COX7B)	−
S70348	integrin beta 3 (ITGB3)	+
U56998	putative serine/threonine protein kinase PRK	+
U33921	HSU33921 cDNA	+
U89336	Notch 4	+
U79287	clone 23867/prostate tumor overexpressed 1 (PTOV1)	−
D88613	HGCMa/glial cells missing homolog 1 (GCM1)	+
L41607	beta-16-N-acetylglucosaminyltransferase (IGNT)	+
S82362	hRAR-beta 2 = retinoic-acid-receptor beta	+
U02566	receptor tyrosine kinase TIF; Also: U18934	−
AF001359	mismatch repair protein (MLH1)/AF001359	−
L27943	cytidine deaminase (CDA)	+
U48405	G prot coupled receptor OGR1	+
M60750	histone H2B.1	+
U15197	histo-blood group ABO protein	+
X13967	leukemia inhibitory factor (LIF/HILDA)	+
U71364	serine protease inhibitor (P19)	+
L42611	keratin 6 isoform K6e (KRT6E)	+
U91930	AP-3 complex delta subunit (AP3D1)	−
L77561	DiGeorge syndrome critical region 11 DGS-D (DGCR11)	+
X90761	Keratin, hair, acidic, 2 hHa2 (KRTHA2)	+
X02176	complement component C9; Also: K02766	−
U22028	cytochrome P450 (CYP2A13)	+
S77583	HERVK10/HUMMTV reverse transcriptase homolog	+
L36529	(clone N5-4) protein p84 (THOC1)	−
M13577	myelin basic protein (MBP)	+
U75272	gastricsin/progastricsin (PGC); Also: J04443	+
D89859	zinc finger 5 protein (ZNF5)	+
Z75330	nuclear protein stromal antigen SA-1 (STAG1)	+
M35416	GTP-binding protein (RALB)	+
S76617	protein tyrosine kinase (BLK)	+
U09303	T cell leukemia LERK-2 (EPLG2)/Ephrin-B1	+
D80004	Hypothetical protein/KIAA0182	+
Z18956	taurine transporter (SLC6A6)	+
AB000464	RES4-24A	+
X13461	calmodulin-like protein (CLP); Also: M58026	+
D79993	Hypothetical/KIAA0171/Enthoprotin (ENTH)	+
Z46632	HSPDE4C1 3,5-cyclic AMP phosphodiesterase (PDE4C)	+
AB002315	Hypothetical protein/KIAA0317	+
X57206	1D-myo-inositol-trisphosphate 3-kinase B (ITPKB)	+
L10717	T cell-specific tyrosine kinase	+
D14889	small GTP-binding protein S10 (RAB33A)	+
U46461	Dishevelled homolog (DVL)	+
L42563	(clone ISW34) non-gastric HK-ATPase (ATP1AL1)	+
M93405	methylmalonate semialdehyde dehydrogenase	+
	(ALDH6A1)
U68233	farnesol receptor (HRR-1)	+
M34181	testis-specific cAMP-dependent prot kinase (PRKACB)	+
L19183	MAC30 hypothetical protein	−
HG2602-	Succinate Dehydrogenase Flavoprotein (HSSUCCDH)	+
HT2698
D28416	esterase D (ESD)	+
L20860	glycoprotein lb beta (GP1BB)	+
L13977	prolylcarboxypeptidase (PRCP)	−
U50553	helicase like protein 2 (DDX3)	+
L14754	DNA-binding protein (SMBP2)	+
Z47727	RNA polymerase II subunit	+
HG3995-	Cpg-Enriched Dna Clone S19	+
HT4265
U61500	GT334 prot (GT334)	+
L19058	glutamate receptor (GLUR5)	+
HG4318-	Lim-Domain Transcription Factor Lim-1 (LHX1);	+
HT4588	U14755
M14159	T-cell receptor beta-chain J2.1	+
K02574	purine nucleoside phosphorylase (PNP)	+
U79261	clone 23959 (MAPK8IP2); Also: U62317	+
D83174	collagen binding prot 2 (SERPINH1); Also: X61598	−
M60626	N-formylpeptide receptor 1 (FPR1)	+
Y09392	WSL-LR, WSL-S1 and WSL-S2 prots; Also: U74611	+
U24704	antisecretory factor-1 (PSMD4)	−
U89505	Hlark	−
D14661	Wims' tumor-1 associating WTAP protein/KIAA0105	+
U05040	FUSE binding protein (FUBP1)	+
S74728	antiquitin (ALDH7A1)	−
U40714	tyrosyl-tRNA synthetase (YARS)	+
M28219	low density lipoprotein receptor	+
Z25535	nuclear pore complex protein hnup153	+
U89896	casein kinase I gamma 2 (CSNK1G2)	+
X71125	glutamine cyclotransferase (QPCT)	+
S72487	Platelet-derived endothelial growth factor 1 (ECGF1)	+

[0034]

TABLE 3
Least discriminatory genes for MS
(on no treatment) vs. Healthy Donors
U78575	phosphatidylinositol 4-phosphate 5-kinase alpha	+
	PIP5K1A
K01884	Blym-1 transforming	+
X75304	Giantin	−
M13699	ceruloplasmin (CP)	+
Z49269	chemokine HCC-1 (CCL14)	+
D28588	Sp2 transcription factor/KIAA0048	+
HG4115-	Olfactory Receptor Or17-210	+
HT4385
HG1751-	CSH5	+
HT1768
L42324	(clone GPCR W) G protein-linked receptor/L42324	+
J03764	Plasminogen activator inhibitor 1	+
Z26256	L-type calcium channel	+
M13955	Mesothelial keratin K7 (KRT7)	+
Y14140	G protein-encoding beta 3 subunit 1 (GNB3)	+
X54871	ras-related prot RAB5B	+
AD000092	RAD23A homolog	+
D13988	rab GDI	+
U58130	Bumetanide-sensitive Na-K-2Cl cotransporter	+
	(NKCC2)
U50743	NaK-ATPase gamma subunit	+
Y13618	DFFRY prot	+
U67932	cAMP phosphodiesterase (PDE7A2); Also: L12052	+
D86967	alpha mannosidase-like protein/KIAA0212	+
X05345	histidyl-tRNA synthetase (HRS)	−
M91036	G-gamma globin (HBG2)	+
U94319	Autoantigen DFS70	+
U02680	protein tyrosine kinase 9 (PTK9)	−
X07203	CD20 receptor (S7)	+
D78361	ornithine decarboxylase antizyme 1 (OAZ1)	+
X98248	Sortilin (SORT1)	+
M93221	macrophage mannose receptor (MRC1)	−
AC002045	Nuclear pore complex-interacting protein (NPIP)	+
D83784	C2 H2-type zinc finger protein/KIAA0198	+
AF005775	caspase-like apoptosis regulatory prot 2 (CLARP)	+
Y10514	CD152 prot (CTLA4); Also: Y10508	−
X80907	phosphatidyl-inositol-3-kinase p85 (PIK3R2)	+
U88666	SFRS protein kinase 2 (SRPK2)	+
HG3104-	Serine Protease MET1	+
HT3280
U63717	osteoclast stimulating factor (OSTF1)	+
D79990	Ras association domain family 2/KIAA0168	+
L32831	G protein-coupled receptor (GPR3); Also: U18550	+
U00238	glutamine PRPP amidotransferase (GPAT)	−
L05425	Autoantigen	−
U71601	zinc finger protein zfp47 (ZNF47)	−
U51010	nicotinamide N-methyltransferase 1 (NNMT); U08021	−
U83410	CUL-2	+
U44799	U1-snRNP binding prot homolog; Also: U44798	+
L07261	alpha adducin (ADD1)	+
X97303	Ptg-12 protein	+
D31797	CD40 ligand (TNFSF5)	+
HG3925-	SFTPA2D	+
HT4195
L15309	zinc finger protein (ZNF141)	+
X13255	dopamine beta-hydroxylase (DBH)	+
Z69043	translocon-associated prot delta subunit	−
	precursor (SSR4)
J04162	leukocyte IgG receptor (Fc-gamma-R)	+
U37431	HOX A1	+
L40397	clone S31i125	−
D10495	protein kinase C delta-type (PRKCD)	+
U20938	Lymphocyte dihydropyrimidine	+
	dehydrogenase (DPYD)
U18919	chromosome 17q12-21 clone pOV-2	−
Y07827	butyrophilin (BTN)/U90552	+
U10868	aldehyde dehydrogenase ALDH7	+
U79252	clone 23679	+
M90299	Glucokinase (GCK)	+
D56495	Reg-related sequence derived peptide-2 (REGL)	+
X66839	MaTu MN p54/58N carbonic anhydrase	+
	9 protein (CA9)
D25217	Membrane protein MLC1/KIAA0027	+
HG2715-	Tyrosine Kinase	+
HT2811
L10338	sodium channel beta-1 subunit	+
	(SCN1B)/U12194, L16242
D87969	CMP-sialic acid transporter (SLC35A1)	+
L20815	S protein/corneodesmosin (CDSN)	+
D87460	Paralemmin/KIAA0270	+
M60830	Ecotropic viral integration site 2B (EVI2B)	+
X06745	DNA polymerase alpha-subunit (POLA)	−
U02683	Nuclear respiratory factor 1 (NRF1); Also:	+
	L22454, U18383
M80629	cdc2-like protein kinase 5 (CDC2L5)	+
U38291	Microtubule-associated prot 1a (MAP1A)	−
D16626	Histidine ammonia lyase (HAL)	+
L39059	TRANSCRIPTION FACTOR SL1 (TAF1C)	−
M31523	transcription factor (E2A)	−
D50926	Hypothetical protein/KIAA0136	+
U82535	fatty acid amide hydrolase (FAAH)	+
U02310	k head domain protein (FKHR)	+
AJ000480	C8FW phosphoprotein	+
HG627-	Rhesus (Rh) Blood Group Ce-Antigen 2, Rhvi/X63097	+
HT5097
S69790	Brush-1 = tumor suppressor	+
U27325	thromboxane A2 receptor (TBXA2R); Also: D38081	+
X66867	MAX	+
X82634	hair keratin acidic 3B (KRTHA3B)	+
HG4018-	Opioid-Binding Cell Adhesion Molecule	+
HT4288
M80244	E16	+
U10886	Protein tyrosine phosphatase (PTPRJ)	+
U51903	RasGAP-related protein (IQGAP2)	+
AF007111	MDM2-like p53-binding protein (MDMX)	+
M32886	sorcin CP-22 (SRI)	−
J04809	Cytosolic adenylate kinase AK1	+
U80811	Lysophosphatidic acid receptor homolog (EDG2)	−
X04445	Inhibin alpha (INHA); Also: M13981	−
X06323	MRL3 ribosomal prot L3 homolog	+
S78432	un-named-transcript-1 from SAS =	−
	transmembrane 4 protein
S71129	acetylcholinesterase (ACHE)	+
X82240	T cell leukemia/lymphoma 1 (TCL1A)	+
Y08999	Sop2p-like protein	−
U51561	cosmid N79E2 sequence	+
D37781	protein-tyrosine phosphatase (PTPRJ); Also: U10886	+
X97230	NK receptor, clone library 4M1#6	+
U48936	amiloride-sensitive epithelial sodium	+
	channel gamma subU
U81006	p76 transmembrane 9 superfamily	+
	member 2 (TM9SF2)
X98534	Vasodilator-stimulated phosphoprotein	+
	(VASP); Z46389
L20859	leukemia virus receptor 1 GLVR1 (SLC20A1)	+
X94563	DBI/ACBP	+
U70323	ataxin-2 (SCA2)	−
U39840	Hepatocyte nuclear factor-3 alpha (HNF-3 alpha)	+
U78190	GTP cyclohydrolase I feedback regulatory	+
	prot (GCHFR)
X55330	aspartylglucosaminidase (AGA)	−
U05237	fetal Alz-50-reactive clone 1 (FAC1)	+
M31210	Endothelial differentiation protein (EDG-1)	+
D63998	golgi alpha-mannosidase II (MAN2A1)	+
U52077	mariner1 transposase complete consensus/U80776	−
U06454	AMP-activated protein kinase (hAMPK)	+
U90916	clone 23815 sequence, IFN-inducible	+
U03399	T-complex protein 10A (TCP10A)	+
HG2668-	Bradykinin Receptor	+
HT2764
L76568	S26 from excision and cross link	−
	repair protein (ERCC4)
HG64-	NF-Kappa B-Binding protein (KBP1)	−
HT64
Z68193	Opsin 1 (OPN1LW)	+
X58298	interleukin-6-receptor (IL6R); Also: M20566	+
Z12962	homolog to yeast ribosomal protein L41	+
Y08265	DAN26 protein; Also: U94836	+
U31248	zinc finger protein (ZNF174)	−
S72503	Inwardly rectifier potassium channel (KCNJ4);	+
	U07364
S76473	tyrosine kinase receptor trkB (NTRK2); U12140	+
K03218	src sarcoma viral oncogene homolog (SRC)	+
Z48923	Bone morphogenetic protein receptor 2 (BMPR2)	+
U21049	Membrane-associated protein 17 (DD96)	+
HG3521-	Ras-Related protein 1b (RAP1B)	+
HT3715
U24685	anti-B cell autoantibody IgM heavy	+
	chain V-D-J region
D45371	GS3109 adipose most abundant gene transcript 1	+
	(APM1)
M17466	blood coagulation factor XII (F12)	−
M80899	novel protein desmoyokin (AHNAK)	+
X83492	Fas/APO1 (TNFRSF6); Also: X63717, X83490	+
U33920	clone lambda 5 semaphorin 3F (SEMA3F)	+
V00594	metallothionein 2A (MT2A); Also: J00271	−
U20428	SNC19 sequence	+
HG4272-	Hepatocyte Growth Factor Receptor	+
HT4542
M30607	zinc finger protein Y-linked (ZFY); Also: L10393	−
M24485	glutathione S-transferase pi (GSTP1); Also: U21689	−
U34976	gamma-sarcoglycan (SGCG)	−
D85376	DNA thyrotropin-releasing hormone receptor (TRHR)	+
D50532	macrophage lectin 2 (HML2)	+
AB000897	cadherin FIB3	+
M29994	alpha-I spectrin (SPNA1); Also: M61877, M61826	+
D42138	Phosphatidylinositol glycan type B (PIG-B)	+
X66142	rod cGMP phosphodiesterase 6b (PDE6B); Also:	+
	S41458
U10686	MAGE-11 antigen (MAGEA11)	+
HG3994-	Cpg-Enriched DNA Clone S16	+
HT4264
X97324	adipophilin (ADFP)	+
U18235	ATP-binding cassette prot (ABC2) HFBCD04 clone	+
X76105	Death-associated protein (DAP1)	−
M65290	Interleukin 12p40 (IL12p40/IL12B)	+
D63160	DNA lectin P35/Ficolin 2 (FCN2)	+
AB006190	aquaporin 6 (AQP6)	+
L42572	p87/89 mitochondrial inner membrane protein (IMMT)	−
U35113	metastasis-associated MTA1	−
U03634	P47 LBC oncoprotein	+
X98253	ZNF183/X98253	+
D90276	CGM7 nonspecific cross-reacting antigen (NCA)	+
Y08263	AAD14 prot	+
HG4102-	N-Ethylmaleimide-Sensitive Factor (NSF)	+
HT4372
HG4638-	Spliceosomal protein Sap 49	+
HT5050
U37408	C-terminal binding protein 1 (CTBP1)	−
HG3748-	Basic Transcription Factor 44 Kda Subunit	+
HT4018
U49835	YKL-39 precursor; chitinase 3-like 2;	+
	U58514, U58515
U37055	hepatocyte growth factor-like	−
	macrophage-stimulating 1
L40395	clone S20iii15	+
X90530	ragB protein	+
M24461	pulmonary surfactant-associated protein SP-B (SFTP3)	+
D13639	G1/S-specific cyclin D2/KIAK0002	+
M35999	platelet glycoprot IIIa/Integrin beta 3 (ITGB3)	+
X13589	aromatase (estrogen synthetase) (CYP19A1)	+
U52827	Cri-du-chat region clone NIBB11	+
X79353	XAP-4 GDP-dissociation inhibitor (GDI1)	−
U00115	zinc-finger protein (BCL6)	−
X78686	Chemokine (C-X-C motif) ligand 5 (CXCL5)	+
HG3627-	Calcium Channel Voltage-Gated Beta 1	+
HT3836	Subunit L Type 2
Y00486	adenine phosphoribosyltransferase (APRT)	+
D50918	septin 2, 6 (SEPT6)/KIAA0128	+
X06318	protein kinase C (PKC) type beta I (PRKCB)	+
X52730	phenylethanolamine n-methyltransferase (PNMT)	+
AB000896	cadherin FIB2	+
X81892	G protein-couped receptor 64 (GPR64)	+
D25538	adenylate cyclase 7 (ADCY7)/KIAA0037	+
X68836	S-adenosylmethionine synthetase (MAT2A)	+
X52638	6-phosphofructo-2-kinase/fructose-26-bisphosphatase	+
L16842	ubiquinol cytochrome-c reductase core I	−
	prot (UQCRC1)
D30758	Centaurin beta 1 (CENTB1)/KIAA0050	+
X53586	integrin alpha 6 VLA6 (ITGA6)	+
X58199	adducin 2 beta (ADD2); Also: S81083_1	+
S50223	HKR-T1 = Kruppel-like zinc finger prot	+
X52011	MYF6 encoding a muscle determination factor	+
D42108	phospholipase C-like 1 (PLCL1)	+
D88795	Cadherin	+
HG3517-	Alpha-1-Antitrypsin	+
HT3711
M16714	MHC class I divergent lymphocyte antigen; clone RS5	+
X76061	p130 retinoblastoma-like 2 (RBL2)	+
U79301	clone 23842 sequence	+
U80040	aconitase nuclear encoded mitochondrial	−
	protein (ACO2)
U82311	unknown protein/U82311	+
U79294	clone 23748 phosphatidic acid phosphatase	+
	2B (PPAP2B)
X99664	prot containing SH3 domain SH3GL3	+
U00928	clone CE29 4.1 (CAC)n/(GTG)n repeat-containing	+
S41458	rod cGMP phosphodiesterase 6B (PDE6B)	+
U06863	follistatin-related protein precursor (FSTL1)	+
HG3884-	Homeotic protein HPX42	−
HT4154
M12759	Ig J chain (IGJ)	+
Y10517	CD108 prot/Y10517	+
U09002	N-methyl-D-aspartate receptor subunit 2A (GRIN2A)	+
HG627-	Rhesus (Rh) Blood Group Ce-Antigenl, 3,	−
HT5098	Rhviii/X63097
M81933	Cell division cycle 25A (CDC25A)	+
X98263	M-phase phosphoprot mpp6	+
U90905	clone 23574 sequence	+
X67683	keratin 4 (KRT4)	+
HG315-	Beta-1-Glycoprot 11 Pregnancy-Specific (PSG11)	+
HT315
M77144	3-b-hydroxysteroid dehydrogenase/5delta-4delta	+
	isomerase
D85418	phosphatidylinositol-glycan-class C (PIGC)	+
M95549	sodium/glucose cotransporter-like protein (SLC5A2)	+
X16665	HOX2H	+
AF002224	E6-AP ubiquitin prot ligase 3A (UBE3A)	+
U12779	MAP kinase activated protein kinase 2 (MAPKAPK2)	+
U07919	aldehyde dehydrogenase 6	+
S85655	prohibitin (PHB)	−
U09087	thymopoietin (TMPO); Also: U09088	+
U72512	B-cell receptor associated protein (hBAP)	+
U52112	Renin binding protein (RENBP)	+
HG4747-	Nadh-Ubiquinone Oxidoreductase 51 Kda Subunit	+
HT5195
AB000450	Vaccinia related kinase 2 (VRK2)	+
X12794	v-erbA related ear-2/NR2F6	+
M19645	78 kdalton glucose-regulated protein (GRP78)	−
M10277	actin (ACTB)	+
D87074	rab3 interacting protein/KIAA0237	+
U58033	myotubularin related prot 2 (MTMR2)/U58033	+
HG2167-	prot Kinase Ht31 cAMP-Dependent	+
HT2237
U41371	spliceosome associated prot (SAP 145)	−
U49395	ionotropic ATP receptor P2X5a	+
X64624	RDC-1 POU domain containing prot; Also: L20433	+
U18548	GPR12 G protein coupled-receptor	+
U55853	130 kD Golgi-localized phosphoprot (GPP130)	+
Z70759	mitochondrial 16S rRNA ()/Z70759	+
L04953	Amyloid precursor protein binding APBA1	+
U68142	RaIGDS-like 2 (RGL2)	+
M16279	MIC2	−
U70732	glutamate pyruvate transaminase (GPT)	+
M31520	Ribosomal S24	−
D28423	pre-splicing factor SRp20	+
X65857	HGMP07E olfactory receptor	+
U30313	diadenosine tetraphosphatase (NUDT2)	−
U78678	thioredoxin 2 (TXN2)	+
J05582	Mucin 1 (MUC1); Also: J05581	−
U85767	myeloid progenitor inhibitory factor-1 (MPIF1)	+
M94172	N-type calcium channel alpha-1 subunit (CACNA1B)	+
AB002559	hunc18b2	+
X62078	GM2 activator protein (GM2A)	−
M62831	TRANSCRIPTION FACTORS ETR101	+
Z18954	S100D calcium binding prot	+
X54816	alpha-1-microglobulin-bikunin (AMBP)	+
M35531	fucosyltransferase (FUT1)	+
M90391	Interleukin 16 (IL16)	+
M87284	69 kDa 2′ oligoadenylate synthetase	−
	(P69 2-5A synthetase)
U91932	AP-3 complex sigma 3A subunit (AP3S1)	−
D87673	heat shock transcription factor 4 (HSF4)	+
D86976	minor histocompatibility antigen HA-1/KIAA0223	+
M82882	cis-acting ELF1	+
D83657	calcium-binding prot in amniotic fluid 1	+
	CAAF1 (S100A12)
U41740	trans-Golgi p230 (GOLGA4)	−
U12535	epidermal growth factor receptor kinase	−
	substrate (EPS8)
HG3635-	Zinc Finger prot, Kruppel-Like	+
HT3845
D50915	hypothetical protein/KIAA0125	+
L04490	NADH-ubiquinone oxidoreductase subunit (NDUFA9)	−
U59748	desert hedgehog (DHH)	+
U82010	heme A: farnesyltransferase (COX10)	−
D50402	Natural resistance associated macrophate	+
	prot1 (NRAMP1)
X16983	integrin alpha-4 subunit VLA4 (ITGA4)	+
U68536	zinc finger protein 45 (ZNF45); Also KOX17	+
X80909	alpha NAC nascent polypeptide-associated complex	−
M24248	MLC-1V-Sb	+
X96401	MAX-binding ROX protein	+
D31888	CoREST protein (RCOR)/KIAA0071	+
X95404	non-muscle type cofilin	−
U09550	oviductal glycoprotein (OVGP1)	+
S79219	metastasis-associated; Also: X14608	−
X65488	Heterogeneous nuclear ribonucleoprotein U (HNRPU)	+
D87685	TFIIS-like PHD finger protein 3/KIAA0244	+
L02840	potassium channel Kv21 (KCNB1)	+
Z19554	vimentin (VIM); Also: M18895_2	−
L36051	Thrombopoietin (THPO)	+
M81758	voltage-dependent sodium channel SKM1 (SCN4A)	+
HG3991-	Cpg-Enriched Dna, Clone E18	+
HT4261
D31846	DRPLA	+
U19906	arginine vasopressin receptor 1 (AVPR1)	+
AB002366	hypothetical protein/KIAA0368	−
M68520	cyclin-dependent kinase 2 (CDK2)	+
U69546	RNA binding prot ETR3	+
U58970	outer mitochondrial membrane translocase (TOMM34)	−
L31584	G prot-coupled receptor (EBI1)	+
X60655	EVX1 homeobox	+
U71300	snRNA activating prot complex 50 kD	+
	subunit (SNAP50)
S75578	4-aminobutyrate aminotransferase (ABAT)	−
X82693	Lymphocyte antigen 6 complex, locus D (E48)	+
HG1155-	Colony-Stimulating Factor 1 Macrophage (CSF1)	+
HT4822
D87432	solute carrier family 7/KIAA0245	+
D50640	phosphodiesterase 3B (PDE3B)	+
D13370	APEX nuclease (APEX1)	+
Z22548	thiol-specific antioxidant peroxiredoxin 2 (PRDX2)	−
M33308	Vinculin (VCL)	−
M80335	protein kinase A catalytic subunit (PRKACA)	+
U14391	myosin-IC	−
Y09943	NGF-inducible PC3 anti-proliferative protein (BTG2)	+
M81780	Sphingomyelin phosphodiesterase 1 (SMPD1)	+
U20582	actin-like peptide (LOC81569)	+
D10656	Sarcoma virus homolog (CRK)	+
Y08319	kinesin-2 (KIF2)	+
Z48633	retrotransposon	−
X15187	homolog of murine tumor rejection	−
	antigen gp96 (TRA1)
HG884-	E6-Associated protein, Papillomavirus	−
	(UBE3A); U84404
HT884
X77753	TROP-2 (TACSTD2)	+
D12620	cytochrome P-450 LTBV; Also: U02388	+
Y09615	mitochondrial transcription termination	+
	factor (MTERF)
J02883	Colipase (CLPS)	+
M81637	Grancalcin (GCA)	+
M61733	erythroid membrane protein 41 (EPB41)	+
U23430	Cholecystokinin type A receptor (CCKAR);	+
	Also: L19315
X95325	DNA binding prot A variant; Also: M24069	−
D87434	Hypothetical protein/KIAA0247	+
HG274-	Gamma-Glutamyltransferase 1 (GGT1); J04131	−
HT274
M98776	keratin 1	+
L20941	ferritin heavy chain (FTH1)	−
D87292	Rhodanese	+
K02766	complement component C9 (C9)	−
X12447	aldolase A (ALDOA) (EC 41213)	−
M59941	GM-CSF receptor beta chain (CSF2RB)	+
D11327	protein tyrosine phosphatase (PTPN7); Also: M64322	+
X90846	mixed lineage kinase 2 (MAP3K10)	+
U33822	tax1-binding prot TXBP181, MAD1-like 1 (MAD1L1)	+
D49410	interleukin 3 receptor alpha subunit (IL3RA)	+
L33842	type II inosine monophosphate	−
	dehydrogenase (IMPDH2)
U57352	sodium channel 1 (hBNaC1)	+
J04444	cytochrome c-1 (CYC1)	−
L13329	iduronate-2-sulfatase (IDS)	+
D50919	TRIM14 protein/KIAA0129	+
L38935	GT212	+
L17327	pre-T/NK cell associated prot (3B3)	+
X04143	bone gla prot (BGP)	−
J05243	nonerythroid alpha-spectrin (SPTAN1)	−
Z11502	annexin A13 (ANXA13)	+
D13637	toll-like receptor 1 (TLR1)/KIAA0012	+
U32680	CLN3	+
D29954	hypothetical protein/KIAA0056	+
M61855	cytochrome P4502C9 (CYP2C9), clone 25	+
U82279	Ig-like transcript 2 (LILRB1)	+
Z83336	hH2B/d	+
U36759	pre-T cell receptor alpha-type chain	+
	precursor (PTCRA)
L13848	RNA helicase A (DDX9)	+
U70862	nuclear factor I/B (NFIB)	+
HG1102-	Ras-Related C3 Botulinum Toxin Substrate (RAC1)	−
HT1102
D85181	fungal sterol-C5-desaturase homolog (SC5DL)	+
M31642	hypoxanthine phosphoribosyltransferase (HPRT)	−
D87470	hypothetical protein/KIAA0280	−
X74330	DNA primase (PRIM1)	+
D28915	hepatitis C-associated protein p44 (IFI44)	+
U82979	Ig-like transcript-3 (LILRB4)	+
HG2480-	Fmlp-Related Receptor I	+
HT2576
HG4263-	NKR-P1A protein	+
HT4533
S77576	ERV9 reverse transcriptase homolog	+
M25629	kallikrein (KLK1)	−
M89957	B cell receptor complex cell surface	+
	glycoprotein (IGB)
X15875	cAMP response element binding prot	−
	CREBP1 (ATF2)
D50550	Lethal giant larvae homolog 1 (LLGL1)	+
U80017	Survival motor neuron protein (SMN)	−
L40387	thyroid receptor interactor TRIP14 (OASL)	+
U34343	13 kD differentiation-associated protein (DAP13)	−
U04270	putative potassium channel subunit (KCNH2)	−
X97160	TFE3 transcription factor from TFE3	+
D83018	NEL-related protein 2 (NELL2)	+
AF008937	syntaxin-16C	+
U38276	semaphorin III family homolog (SEMA3F)	−
X83368	phosphatidylinositol 3 kinase gamma (PIK3CG)	+
X59739	Zinc finger protein, X-linked (ZFX)	+
J02611	apolipoprotein D	+
X13293	v-myb myeloblastosis viral homolog-like 2 (MYBL2)	−

[0035]

TABLE 4
Highly discriminatory genes for MS (regardless of
treatment with Avonex or not) vs. Healthy Donors
Probe sets	Gene Descriptions	Up (+) or down (−)
Z16411	phospholipase c; Also: U26425, Z37544 (PLCB3)	−
U78095	Placental bikunin (AMBP)	+
L34075	FKBP-rapamycin associated prot (FRAP)	+
X90857	(−14) containing globin regulatory element (CGTHBA)	−
HG644-	Histone H1.1 (HIST1H1A)	−
HT644
D86043	SHPS-1/PTPNS1 tyrosine phosphatase; Also: U06701	−
Z49254	L23-related MRPL23	−
M21259	Alu repeats in the region to the small nuclear ribonucleoprot E	−
X13444	CD8 beta-chain glycoprot (CD8 beta1)	+
Y00282	ribophorin II (RPN2)	−
S74728	antiquitin (ALDH7A1)	−
U79303	clone 23882	+
U15197	Histo-blood group ABO prot	+
M76424	carbonic anhydrase VII (CA VII)	+
M29971	6-O-methylguanine-DNA methyltransferase (MGMT)	−
X16316	vav oncogene	+
D83174	collagen binding prot 2 (SERPINH1); Also: X61598	−
U07550	Chaperonin 10 (HSPE1)	−
U39318	E2 ubiquitin conjugating enzyme UbcH5C (UBCH5C)	+
L42324	(clone GPCR W) G prot-linked receptor/L42324	+
L19593	IL-8 receptor beta (IL8RB)	+
M98833	ERGB TRANSCRIPTION FACTORS (FLI-1 homolog)	+
M93221	macrophage mannose receptor (MRC1)	−
M14159	T-cell receptor beta-chain J2.1	+
X05345	histidyl-tRNA synthetase (HRS)	−
U66059	TCRBV1S1A1N1 from germline T-cell receptor beta chain	+
D79993	Hypothetical/KIAA0171/Enthoprotin (ENTH)	+
U24704	antisecretory factor-1 (PSMD4)	−
X72879	14A2AK DNA sequence	+
D29675	Inducible nitric oxide synthase (iNOS)	+
U94319	autoantigen DFS70	+
HG3175-	Carcinoembryonic Antigen	+
HT3352
L20859	leukemia virus receptor 1 GLVR1 (SLC20A1)	+
K01884	Blym-1 transforming	+
S76992	VAV2 = VAV onco homolog	+
HG2415-	Transcription Factor E2f-2	+
HT2511
L76200	guanylate kinase (GUK1)	−
M25269	tyrosine kinase (ELK1) onco	+
X05309	C3b/C4b receptor (CR1) F allotype.	+
AC002486	BAC clone RG367O17/7p15-p21/AC002486	+
U79528	SR31747 binding prot 1 (SRBP1); Also: U75283	+
U89896	casein kinase I gamma 2 (CSNK1G2)	+
X66867	MAX	+
Y09392	WSL-LR, WSL-S1 and WSL-S2 prots; Also: U74611	+
Z15114	protein kinase C gamma (PRKCG)	+
L36922	Met-ase 1/Granzyme M (GZMM)	+
U79287	clone 23867/prostate tumor overexpressed 1 (PTOV1)	−
M31523	transcription factor (E2A)	−
U37055	hepatocyte growth factor-like/L11924, M74178, U28055	−
U52077	mariner1 transposase complete consensus sequence/U80776	−
D86979	hypothetical protein/KIAA0226	+
D26579	transmembrane prot ADAM8	+
Y09443	alkyl-dihydroxyacetonephosphate synthase AGPS	+
U79262	deoxyhypusine	+
U51903	RasGAP-related prot (IQGAP2)	+
M60830	Ecotropic viral integration site 2B (EVI2B)	+
U53347	neutral amino acid transporter B (SLC1A5)	+
D79990	Ras association domain family 2/KIAA0168	+
Z47038	microtubule-associated; prot 1A (MAP1A)/U38291_rna1	+
U30313	diadenosine tetraphosphatase (NUDT2)	−
D26069	Centaurin beta 2 (CENTB2)/KIAA0041	+
Z69043	translocon-associated prot delta subunit precursor (SSR4)	−
U02683	Nuclear respiratory factor 1 (NRF1); Also: L22454, U18383	+
U46461	dishevelled homolog (DVL)	+
U47635	D13S824E locus	−
HG3991-	Cpg-Enriched Dna, Clone E18	+
HT4261
L27943	cytidine deaminase (CDA)	+
U34976	gamma-sarcoglycan (SGCG)	−
U31248	zinc finger prot (ZNF174)	−
U18271	thymopoietin (TMPO); Also: U09087, U09088	+
HG627-	Rhesus (Rh) Blood Group Ce-Antigenl, 3, Rhviii; Also: X63097	−
HT5098
M19650	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
HG3730-	Tyrosine Kinase Syk; Also: L28824	+
HT4000
D13988	rab GDI	+

[0036]

TABLE 5
Intermediate discriminatory genes for MS
(regardless of treatment with Avonex
or not) vs. Healthy Donors
D10495	protein kinase C delta-type (PRKCD)	+
D64158	cell differentiation-associated ATP binding prot	+
U78521	immunophilin homolog ARA9	+
D30037	phosphatidylinositol transfer protein (PITPN)	+
U33921	HSU33921 cDNA	+
HG2825-	Ret Transforming	+
HT2949
L34357	GATA-4	+
L16842	ubiquinol cytochrome-c reductase core I	−
	prot (UQCRC1)
D16626	Histidine ammonia lyase (HAL)	+
U48405	G prot coupled receptor OGR1	+
Y10514	CD152 prot (CTLA4); Also: Y10508	−
HG3521-	Ras-Related prot 1b	+
HT3715
D86967	alpha mannosidase-like protein/KIAA0212	+
HG4318-	Lim-Domain Transcription Factor Lim-1	+
HT4588	(LHX1); U14755
X75304	giantin	−
M19645	78 kdalton glucose-regulated prot (GRP78)	−
AB000464	RES4-24A	+
U14187	receptor tyrosine kinase ligand LERK-3/Ephrin-A3	+
Z26256	L-type calcium channel/Z26256	+
U34301	nonmuscle myosin heavy chain IIB/U34301	+
HG4108-	Olfactory Receptor Or17-24	+
HT4378
X07619	cytochrome P450 db1 variant b; Also: X16866	+
Z14244	coxVllb cytochrome c oxidase subunit VIIb (COX7B)	−
M90299	glucokinase (GCK)	+
D78361	ornithine decarboxylase antizyme 1 (OAZ1)	+
M62831	TRANSCRIPTION FACTORS ETR101	+
U50553	helicase like protein 2 (DDX3)	+
D31883	actin-binding LIM protein 1 (ABLIM1)/KIAA0059	+
U44799	U1-snRNP binding prot homolog; Also: U44798	+
U80811	Lysophosphatidic acid receptor homolog (EDG2)	−
D31797	CD40 ligand (TNFSF5)	+
U89336	Notch 4	+
L04490	NADH-ubiquinone oxidoreductase subunit (NDUFA9)	−
X52943	ATF-a TRANSCRIPTION FACTORS	−
U91930	AP-3 complex delta subunit (AP3D1)	−
U12535	epidermal growth factor receptor kinase	−
	substrate (EPS8)
X83492	Fas/APO1 (TNFRSF6)	+
U89505	Hlark	−
U59752	Sec7p-like prot	+
X15187	tra1 homolog of murine tumor rejection antigen gp96	−
X72964	caltractin	−
X58298	interleukin-6-receptor (IL6R); Also: M20566	+
U41371	spliceosome associated prot (SAP 145)	−
U02310	k head domain prot (FKHR)	+
X98248	Sortilin (SORT1)	+
D50640	phosphodiesterase 3B (PDE3B)	+
D55696	cysteine protease	−
Z46632	HSPDE4C1 3,5-cyclic AMP	+
	phosphodiesterase (PDE4C)
Y09022	Not56-like protein (NOT56L)	+
M32886	sorcin CP-22 (SRI)	−
D16217	Calpastatin (CAST)	+
D83018	nel-related prot 2	+
U76388	steroidogenic factor 1 (NR5A1)	+
S85655	prohibitin (PHB)	−
L33842	(clone FFE-7) type II inosine	−
	monophosphate dehydrogenase
Z49269	chemokine HCC-1 (CCL14)	+
U63717	osteoclast stimulating factor (OSTF1)	+
M82882	cis-acting ELF1	+
D45132	kidney zinc-finger DNA-binding protein PRDM2	+
Z18956	taurine transporter (SLC6A6)	+
U03398	receptor 4-1BB ligand (TNFSF9)	+
L05512	histatin 1 (HTN1)	+
U82010	heme A: farnesyltransferase (COX10)	−
U20428	SNC19 sequence	+
U69546	RNA binding prot ETR3	+
S72503	HRK1 = inward rectifier potassium	+
	channel; Also: U07364
M80335	protein kinase A catalytic subunit (PRKACA)	+
U22028	cytochrome P450 (CYP2A13)	+
M75099	Rapamycin and FK506-binding protein FKBP13	−
U68536	zinc finger protein 45 (ZNF45); Also KOX17	+
AB001325	Aquaporin 3 (AQP3)	+
X65977	corticostatin HP-4 precursor (defensin/DEFA4)	+
HG2167-	prot Kinase Ht31 Camp-Dependent	+
HT2237
L21936	succinate dehydrogenase flavoprot subunit (SDH)	−
L40397	(clone S31i125)	−
AC002073	WUGSC: DJ515N12/PAC clone	+
	DJ515N1/22q112-q22
D86976	minor histocompatibility antigen HA-1/KIAA0223	+
D28416	esterase D (ESD)	+
D30036	phosphatidylinositol transfer protein (PITPN)	+
X15875	cAMP response element binding prot CREBP1 (ATF2)	−
U90913	clone 23665 sequence	−
L33243	polycystic kidney disease 1 prot (PKD1)	−
U80628	thymidine kinase 2 isom B (TK2) alternatively spliced	−
U02566	receptor tyrosine kinase TIF; Also: U18934	−
D87460	paralemmin/KIAA0270	+
D11327	protein tyrosine phosphatase (PTPN7); Also: M64322	+
D87450	parallel sister chromatids drosophila	+
	protein-like/KIAA0261
HG1862-	Calmodulin Type I	+
HT1897
AF005775	caspase-like apoptosis regulatory prot 2 (CLARP)	+
X75755	PR264; Also: HG3088-HT3261 Same	+
	Uni Cluster as M90104
X57206	1D-myo-inositol-trisphosphate 3-kinase B (ITPKB)	+
U80040	aconitase nuclear encoded mitochondrial prot	−
D86964	dedicator of cytokinesis 1 homolog protein/KIAA0209	+
U40714	tyrosyl-tRNA synthetase (YARS)	+
X67235	proline rich homeobox (Prh) prot; Also: L16499	+
AC002045	Nuclear pore complex-interacting protein (NPIP)	+
Z22548	thiol-specific antioxidant peroxiredoxin 2 (PRDX2)	−
D28423	pre-splicing factor SRp20	+
S75578	4-aminobutyrate aminotransferase (ABAT)	−
HG3995-	Cpg-Enriched Dna Clone S19	+
HT4265
M24485	glutathione S-transferase pi (GSTP1); Also: U21689	−
M93405	methylmalonate semialdehyde	+
	dehydrogenase (ALDH6A1)
L36529	(clone N5-4) protein p84 (THOC1)	−
L77561	DiGeorge syndrome critical region 11	+
	DGS-D (DGCR11)
D83920	uterus ficolin-1	+
X63679	TRAMP prot	+
D30758	Centaurin beta 1 (CENTB1)/KIAA0050	+
HG2715-	Tyrosine Kinase	+
HT2811
D50925	serine-threonine protein kinase/KIAA0135	+
L42572	p87/89 mitochondrial inner membrane protein (IMMT)	−
U25975	serine kinase (hPAK65)	+
HG2479-	Helix-Loop-Helix prot Sef2-1d; Also: M74719	+
HT2575
X76648	glutaredoxin	+
D82345	NB thymosin beta	−
M13994	bcl-2-alpha; Also: M14745	+
D13639	G1/S-specific cyclin D2/KIAK0002	+
L39059	TRANSCRIPTION FACTOR SL1 (TAF1C)	−
M81933	Cell division cycle 25A (CDC25A)	+
X57809	rearranged Ig lambda light chain	+
U41740	trans-Golgi p230 (GOLGA4)	−
D83784	C2 H2-type zinc finger protein/KIAA0198	+
HG4272-	Hepatocyte Growth Factor Receptor	+
HT4542
M34181	testis-specific cAMP-dependent prot	+
	kinase (PRKACB)
X79353	XAP-4 GDP-dissociation inhibitor (GDI1)	−
U20938	Lymphocyte dihydropyrimidine	+
	dehydrogenase (DPYD)
M58285	membrane-associated prot (HEM-1)	+
L15309	zinc finger prot (ZNF 141)	+
J04444	cytochrome c-1 (CYC1)	−
Y08265	DAN26 prot; Also: U94836	+
D50532	macrophage lectin 2 (HML2)	+
U43030	cardiotrophin-1 (CTF1)	+
AB000450	Vaccinia related kinase 2 (VRK2)	+
U73377	p66shc (SHC)	−
X62654	ME491/CD63 antigen	−
HG3570-	prot Phosphatase Inhibitor Homolog	−
HT3773
U78575	phosphatidylinositol 4-phosphate 5-kinase	+
	alpha PIP5K1A
M63573	secreted cyclophilin-like prot (SCYLP)	−
D31767	DAZ associated protein 2/KIAA0058	+
X94563	dbi/acbp/X94563	+
D31846	DRPLA	+
U20647	zinc finger prot (ZNF151)	+
X89101	Fas/APO1 (TNFRSF6)	+
U31903	CREB-RP (CREBL1); Also: U89337_1, X98054	+
HG315-	Beta-1-Glycoprot 11 Pregnancy-Specific (PSG11)	+
HT315
X75252	phosphatidylethanolamine binding prot	−
Z48042	encoding GPI-anchored prot p137	+
M20778	alpha-3 (VI) collagen; Also: X52022	+
M81118	alcohol dehydrogenase chi polypeptide (ADH5)	−
X76105	Death-associated protein (DAP1)	−
M16279	MIC2	−
D83779	Hypothetical protein/KIAA0195	+
U07231	G-rich sequence factor-1 (GRSF-1)	−
M28713	NADH-cytochrome b5 reductase (b5R)	−
X16609	ankyrin (variant 2.1); Also: HG2737-HT2837	−
D87434	Hypothetical protein/KIAA0247	+
Y08409	spot14	+
D87735	ribosomal prot L14	+
M35416	GTP-binding prot (RALB)	+
S79219	metastasis-associated; Also: X14608	−
U59309	fumarase precursor (FH)	−
D28588	Sp2 transcription factor/KIAA0048	+
X94910	ERp31 prot	+
M34175	beta adaptin	+
X71125	glutamine cyclotransferase (QPCT)	+
AF006087	Arp2/3 prot complex subunit p20-Arc (ARC20)	+
U43431	DNA topoisomerase III alpha (TOP3A)	−
D38491	Hypothetical protein/KIAA0117	+
U30521	P311 HUM-31	−
U03634	P47 LBC onco	+
M13955	mesothelial keratin K7 (type II)	+
S78432	un-named-transcript-1 from SAS = transmembrane 4	−
K03218	src sarcoma viral oncogene homolog (SRC)	+
L04270	(clone CD18) tumor necrosis factor	−
	receptor 2 related prot
U38291	microtubule-associated prot 1a (MAP1A)	−
	genomic sequence
U78027	L44L (L44-like ribosomal prot)	+
U09303	T cell leukemia LERK-2 (EPLG2)/Ephrin-B1	+
AB002365	Hypothetical protein/KIAA0367	−
AD000092	RAD23A homolog	+
U49395	ionotropic ATP receptor P2X5a	+
U70732	glutamate pyruvate transaminase (GPT)	+
U41068	retinoid X receptor beta (RXRbeta)/collagen	+
	alpha2(XI)
Z25884	CIC-1 muscle chloride channel protein (CLCN1)	+
X65488	Heterogeneous nuclear ribonucleoprotein U (HNRPU)	+
M63959	alpha-2-macroglobulin receptor-associated prot	−
U14391	myosin-IC	−
M10277	cytoplasmic beta-actin; Also: HSAC07/X00351	+
D25217	Membrane protein MLC1/KIAA0027	+
D87969	CMP-sialic acid transporter (SLC35A1)	+
M83221	I-Rel	+
M12759	Ig J chain (IGJ)	+
X76534	NMB	−
Z48923	BMPR-II	+
M31520	Ribosomal S24	−
U15173	Nip2 (NIP2)	+
AB002559	hunc18b2	+
U49837	LIM prot MLP (CSRP3)	+
X02761	fibronectin (FN precursor); Also: HG3044-HT2527	−
L14754	DNA-binding prot (SMBP2)	+
AF008937	syntaxin-16C	+
U58032	myotubularin related prot 1 (MTMR1)/U58032	+
Z12962	homolog to yeast ribosomal prot L41	+
U88964	HEM45	+
X98534	Vasodilator-stimulated phosphoprotein	+
	(VASP); Z46389
S75463	P43 = mitochondrial elongation factor homolog	−
Y09980	HOXD3	−
U48936	amiloride-sensitive epithelial sodium	+
	channel gamma subunit
M15841	U2 small nuclear RNA-associated B′ antigen	−
Z18951	caveolin	−
D86965	Hypothetical protein/KIAA0210	+
L19058	glutamate receptor (GLUR5)	+
U77594	tazarotene-induced 2 (TIG2)	−
M55543	guanylate binding prot isom II (GBP-2)	−

[0037]

TABLE 6
Least discriminatory genes for MS (regardless
of treatment with Avonex or not) vs. Healthy Donors
HG4018-	Opioid-Binding Cell Adhesion Molecule	+
HT4288
X79683	Z68155 and others	−
M29696	interleukin-7 receptor (IL-7)	+
L16896	zinc finger prot	−
Y00285	insulin-like growth factor II receptor; Also: J03528	−
HG4115-	Olfactory Receptor Or17-210	+
HT4385
L32977	ubiquinol cytochrome c reductase Rieske iron-sulphur prot	−
M65290	Interleukin 12p40 (IL12p40/IL12B)	+
U15131	p126 (ST5)	−
L48513	paraoxonase 2 (PON2)	−
M31642	hypoxanthine phosphoribosyltransferase (HPRT)	−
M83088	phosphoglucomutase 1 (PGM1)	−
U83410	CUL-2 (cul-2)	+
U41804	putative T1/ST2 receptor binding prot precursor	−
U57094	small GTP-binding prot	+
U05040	FUSE binding protein (FUBP1)	+
L20815	S protein/corneodesmosin (CDSN)	+
X66142	rod cGMP phosphodiesterase 6b (PDE6B); Also: S41458	+
X53586	integrin alpha 6	+
L25286	alpha-1 type XV collagen; Also: L25285	−
J03764	Plasminogen activator inhibitor 1	+
Z38026	FALL-39 peptide antibiotic	−
U27325	thromboxane A2 receptor (TBXA2R); Also: D38081	+
HG4747-	Nadh-Ubiquinone Oxidoreductase 51 Kda Subunit	+
HT5195
L40395	(clone S20iii15)	+
L40387	thyroid receptor interactor TRIP14 (OASL)	+
M31210	Endothelial differentiation protein (EDG-1)	+
X56741	rab8	+
Z84497	from cosmid O14 on chrom 6 contains RING3, CpG Island	+
L76568	S26 from excision and cross link repair prot (ERCC4)/L76568	−
S77583	HERVK10/HUMMTV reverse transcriptase homolog/S77583	+
M64099	gamma-glutamyl transpeptidase-related prot (GGT-Rel)	−
L35253	p38 mitogen activated prot (MAP) kinase; Also: L35264	+
S82362	hRAR- beta 2 = retinoic-acid-receptor beta/M62303	+
U00238	glutamine PRPP amidotransferase (GPAT)	−
U79526	orphan G-prot coupled receptor Dez isoform a	−
HG4114-	Olfactory Receptor Or17-209	+
HT4384
L31584	G prot-coupled receptor (EBI1)	+
X07203	CD20 receptor (S7)	+
Y07701	aminopeptidase	+
X13839	vascular smooth muscle alpha-actin	−
D28114	myelin-associated oligodendrocytic basic protein (MOBP)	+
HG3994-	Cpg-Enriched Dna Clone S16	+
HT4264
X78520	CLCN3	−
AF006084	Arp2/3 prot complex subunit p41-Arc (ARC41)	+
U33920	clone lambda 5 semaphorin 3F (SEMA3F)	+
M81637	Grancalcin (GCA)	+
X89267	DNA uroporphyrinogen decarboxylase (UROD)	+
X82200	Staf50	+
Z70759	mitochondrial 16S rRNA ()/Z70759	+
X78925	HZF2 zinc finger prot	+
Y00486	adenine phosphoribosyltransferase (aprt)	+
X59871	TCF-1 T cell factor 1	+
U50743	NaK-ATPase gamma subunit	+
U06454	AMP-activated prot kinase (hAMPK)	+
X75593	rab 13	−
U68233	farnesol receptor HRR-1 (HRR-1)	+
HG2602-	Succinate Dehydrogenase Flavoprotein (HSSUCCDH)	+
HT2698
D25304	Rac/Cdc42 guanine exchange factor/KIAA0006	+
HG884-	Oncogene E6-Ap, Papillomavirus; Also: U84404	−
HT884
U40705	telomeric repeat binding factor (TRF1)	−
D42046	DNA replication helicase-like homolog/KIAA0083	+
U63541	expressed in HC/HCC livers and MolT-4 proliferating cells	+
HG417-	Cathepsin B; Also: L22569	−
HT417
HG4258-	Kinase Inhibitor P27kip1 Cyclin-Dependent	+
HT4528
Y10936	hypothetical prot downstream of DMPK and DMAHP	+
D28364	annexin II (ANXA2)	+
D29833	salivary proline rich peptide P-B	+
U10886	Protein tyrosine phosphatase (PTPRJ)	+
M13699	ceruloplasmin (CP)	+
U24183	phosphofructokinase (PFKM); Also: HG1849-HT1878	−
U43083	G alpha-q (Gaq)	+
D83657	calcium-binding prot in amniotic fluid 1 CAAF1 (S100A12)	+
Y13618	DFFRY prot	+
U60060	FEZ1	−
U03399	T-complex prot 10A (TCP10A)	+
X68836	S-adenosylmethionine synthetase (MAT2A)	+
M81758	voltage-dependent sodium channel SKM1 (SCN4A)	+
J02611	apolipoprot D	+
M13577	myelin basic prot (MBP)	+
M73077	glucocorticoid receptor repression factor 1 (GRF-1)	−
X16983	integrin alpha-4 subunit VLA4 (ITGA4)	+
AF002224	E6-AP ubiquitin prot ligase 3A (UBE3A)	+
HG3638-	Amyloid Beta (A4) Precursor prot; Also: Y00264	−
HT3849
L07758	IEF SSP 9502	−
M87507	interleukin-1 beta convertase (IL1BCE); Also: U13697	+
Y00062	T200 leukocyte common antigen (CD45 LC-A)	+
M81750	myeloid cell nuclear differentiation antigen	+
X06825	skeletal beta-tropomyosin	−
U07919	aldehyde dehydrogenase 6	+
D88613	HGCMa/glial cells missing homolog 1 (GCM1)	+
U17969	initiation factor eIF-5A	−
M31013	nonmuscle myosin heavy chain (NMHC)	−
M57763	ADP-ribosylation factor (hARF6)	+
X76061	p130 retinoblastoma-like 2 (RBL2)	+
AF007111	MDM2-like p53-binding prot (MDMX)	+
K02574	purine nucleoside phosphorylase (PNP)	+
X90761	Keratin, hair, acidic, 2 hHa2 (KRTHA2)	+
D49490	disulfide isomerase-related protein (PDIR)	+
L12350	thrombospondin 2 (THBS2)	−
X96506	NC2 alpha subunit; Also: U41843	+
L19183	MAC30	−
D86971	Hypothetical protein/KIAA0217	+
L42563	(clone ISW34) non-gastric HK-ATPase (ATP1AL1)	+
D25538	adenylate cyclase 7 (ADCY7)/KIAA0037	+
L06633	TRANSCRIPTION FACTORS	+
M77349	transforming growth factor-beta induced product (BIGH3)	−
Z35093	SURF-1	−
L06845	cysteinyl-tRNA synthetase	+
HG3627-	Calcium Channel Voltage-Gated Beta 1 Subunit L Type 2	+
HT3836
X55330	aspartylglucosaminidase (AGA)	−
U75272	gastricsin/progastricsin (PGC); Also: J04443	+
J04162	leukocyte IgG receptor (Fc-gamma-R)	+
Z29505	nucleic acid binding prot sub23	+
M86406	skeletal muscle alpha 2 actinin (ACTN20	−
U67963	lysophospholipase homolog (HU-K5)	−
S69272	38 kda intracellular serine protase inhibitor; Also: Z22658	−
S82297	beta 2-microglobulin	+
S50017	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
K02777	T-cell receptor active alpha-chain from Jurkat cell line/M12959	+
M27749	Ig-related 14.1 prot	+
M55621	N-acetylglucosaminyltransferase I (GlcNAc-TI)	+
X52011	MYF6 encoding a muscle determination factor	+
HG2815-	Myosin, Light Chain/U02629; Also: HG2815-HT1357, M22919	−
HT2931
HG3884-	Homeotic protein HPX42	−
HT4154
D87470	hypothetical protein/KIAA0280	−
D37781	protein-tyrosine phosphatase (PTPRJ); Also: U10886	+
U41766	metalloprotease/disintegrin/cysteine-rich prot precursor MDC9	−
Z11559	iron regulatory factor	−
U34380	prot tyrosine kinase TEC and TXK; Also: D29767	+
X68486	A2a adenosine receptor	+
M19267	tropomyosin; Also: X12369	−
M64497	apolipoprot AI regulatory prot (ARP-1)	−
Z24727	tropomyosin isoform	−
Y09836	unknown prot	−
D80006	Hypothetical protein/KIAA0184	+
U78678	thioredoxin 2 (TXN2)	+
HG4094-	Transcription Factor Lsf-Id; Also: U03494	+
HT4364
L10717	T cell-specific tyrosine kinase	+
U22431	hypoxia-inducible factor 1 alpha; X72726, U29165	−
U07857	18 kDa Alu RNA binding prot	−
X97303	Ptg-12 prot/X97303	+
X98172	MACH alpha 1 prot	+
L35240	enigma	−
Z74616	prepro-alpha2(l) collagen; Also: J03464	−
D56495	Reg-related sequence derived peptide-2 (REGL)	+
U52827	Cri-du-chat region clone NIBB11	+
HG1751-	CSH5	+
HT1768
Y10517	CD108 prot/Y10517	+
M37721	peptidylglycine alpha-amidating monooxygenase	−
D87716	hypothetical protein KIAA0007; Also: D26488	−
U83908	nuclear antigen H731	+
D38024	facioscapulohumeral muscular dystrophy (FSHD)	+
HG2755-	T-Plastin	−
HT2862
U65579	mitoch NADH dehydrogenase-ubiquinone Fe-S prot	−
U05237	fetal Alz-50-reactive clone 1 (FAC1)	+
D12620	cytochrome P-450LTBV; Also: U02388	+
L10413	farnesyltransferase alpha-subunit	−
D87445	Hypothetical protein/KIAA0256	+
U33822	tax1-binding prot TXBP181, MAD1-like 1 (MAD1L1)	+
S81957	BMP-5 = bone morphogenic prot-5/S81957	+
L06499	ribosomal prot L37a (RPL37A)	+
D86957	Septin-like protein/KIAA0202	−
U73477	acidic nuclear phosphoprot pp32; Also: X75090	+
M22632	mitochondrial aspartate aminotransferase	−
X60188	ERK1 prot serine/threonine kinase	−
AF001359	mismatch repair prot (hMLH1)/AF001359	−
Z68193	Opsin 1 (OPN1LW)	+
U82311	unknown prot/U82311	+
U34044	selenium donor prot (seID)	−
U55206	gamma-glutamyl hydrolase (hGH)	−
U90916	clone 23815 sequence, IFN-inducible	+
M16424	beta-hexosaminidase alpha chain (HEXA)	+
U46025	translation initiation factor elF-3 p110 subunit	−
M90391	Interleukin 16 (IL16)	+
U49835	YKL-39 precursor; Also: U58514, U58515	+
HG2668-	Bradykinin Receptor	+
HT2764
Z11793	selenoprot P	−
X64364	M6 antigen	−
M58028	ubiquitin-activating enzyme E1 (UBE1)	−
X66839	MaTu MN p54/58N carbonic anhydrase 9 protein (CA9)	+
L17327	pre-T/NK cell associated prot (3B3)	+
X80692	ERK3	−
U09550	oviductal glycoprotein (OVGP1)	+
X64330	ATP-citrate lyase	−
U81006	p76 transmembrane 9 superfamily member 2 (TM9SF2)	+
Y09943	NGF-inducible PC3 anti-proliferative protein (BTG2)	+
U70862	nuclear factor I/B (NFIB)	+
U24685	anti-B cell autoantibody lgM heavy chain variable V-D-J region	+
HG3991-	Cpg-Enriched Dna, Clone E18	+
HT4261
80343	ArgRS = arginyl-tRNA synthetase	−
U37146	silencing mediator of retinoid and thyroid hormone SMRT	−
U47101	NifU-like prot (hNifU)	−
M13241	N-myc	−
M24899	triiodothyronine (ear7)	−
AB000896	cadherin FIB2	+
M19283	cytoskeletal gamma-actin	−
L25085	Sec61-complex beta-subunit	−
L07261	alpha adducin (ADD1)	+
S65738	actin depolymerizing factor	−
D14889	small GTP-binding protein S10 (RAB33A)	+
U40462	Ikaros/LyF-1 homolog (hlk-1)	+
M26730	mitochondrial ubiquinone-binding prot; Also: X13585, M22348	−
M28219	low density lipoprot receptor (FH 10)	+
X52192	RNA c-fes	+
L76571	nuclear hormone receptor (shp)	−
M76378	cysteine-rich prot (CRP)	−
AB006190	aquaporin 6 (AQP6)	+
M54995	connective tissue activation peptide III	+
U51561	cosmid N79E2 sequence	+
U29680	A1 prot	+
AB000584	TGF-beta superfamily prot	+
HG3517-	Alpha-1-Antitrypsin	+
HT3711
X52599	beta nerve growth factor	+
U89922	lymphotoxin beta isoform variant/L11016_rna1, L11015	+
AB000897	cadherin FIB3	+
HG627-	Rhesus (Rh) Blood Group Ce-Antigen, 2, Rhvi; Also: X63097	+
HT5097
D89859	zinc finger 5 protein (ZNF5)	+
X63422	delta-subunit of mitochondrial F1F0 ATP-synthase (clone #1)	−
X98253	ZNF183/X98253	+
M37104	mitochondrial ATPase coupling factor 6 subunit (ATP5A)	−
X57809	rearranged Ig lambda light chain; Also: S42404	+
M31899	DNA repair helicase (ERCC3)	−
X16663	HS1 heamatopoietic lineage cell specific prot	+
D86960	Hypothetical protein/KIAA0205	+
X06700	pro-alpha1(III) collagen; Also: X14420	−
X12794	v-erbA related ear-2/NR2F6	+
L10338	sodium channel beta-1 subunit (SCN1B)/U12194, L16242	+
L38935	GT212	+
U52101	desmocollin-2 3	+
U35113	metastasis-associated mta1	−
X02875	(2-5 ) oligo A synthetase E (1,8 kb RNA); Also: M11810_2	+
Z29083	5T4 Oncofetal antigen	−
X69141	squalene synthase	−
D80004	Hypothetical protein/KIAA0182	+
M29994	alpha-I spectrin (SPNA1); Also: M61877, M61826	+
D42073	reticulocalbin	−
X90846	mixed lineage kinase 2 (MAP3K10)	+
L13329	iduronate-2-sulfatase (IDS)	+
U09813	mitochondrial ATP synthase subunit 9 P3	−
M91029	AMP deaminase (AMPD2)	+
HG2815-	HG2815-HT2931_at	−
HT2931
Z78289	(clone 1D2)/Z78289	+
M23114	calcium-ATPase (HK1)	−
U10686	MAGE-11 antigen (MAGE11)	+
M15395	leukocyte adhesion prot (LFA-1/Mac-1/p150,95 family)	+
M19045	lysozyme	+
X96401	MAX-binding ROX protein	+
M33336	cAMP-dependent prot kinase type I-alpha subunit (PRKAR1A)	+
D13626	G protein-coupled receptor/KIAA0001	−
U71300	snRNA activating prot complex 50 kD subunit (SNAP50)	+
J02854	20-kDa myosin light chain (MLC-2)	−
AJ000480	C8FW phosphoprot	+
U40998	retinal prot (HRG4)	+
HG3893-	Phosphoglucomutase 1	+
HT4163
X17567	snRNP prot B; Also: J04564	−
D42108	phospholipase C-like 1 (PLCL1)	+
U79271	clones 23920 and 23921 sequence	−
M94046	zinc finger prot (MAZ)	−
X89067	trpc2 transcript (possible pseudo)	+
X57398	pM5 prot	−
HG2649-	Serine/Threonine prot Kinase Cdk3; Also: X66357	−
HT2745
U82535	fatty acid amide hydrolase (FAAH)	+
X59798	PRAD1 cyclin	−
HG2480-	Fmlp-Related Receptor I	+
HT2576
U18009	chromosome 17q21 clone LF113	−
M64571	microtubule-associated prot 4	−
D82344	NBPhox (PHOX2B)	+
X61587	rhoG GTPase	+
M35531	fucosyltransferase (FUT1)	+
HG4322-	Tubulin, Beta	−
HT4592
M55210	laminin B2 chain (LAMB2)	−
X95735	zyxin 2	−
L42176	(clone 353) DRAL	−
X60036	mitochondrial phosphate carrier prot	−
X57766	stromelysin-3	−
HG4683-	TNF Receptor 2 Associated prot Trap3/U12597	−
HT5108
L26339	autoantigen	−
D38437	DNA mismatch repair	−
S67798	PH-20	+
Z47727	RNA polymerase II subunit	+
U68142	RalGDS-like 2 (RGL2)	+
D87436	Lipin 2/KIAA0249	+
Z19554	vimentin (VIM); Also: M18895_2	−
J00123	enkephalin	−
D42138	Phosphatidylinositol glycan type B (PIG-B)	+
M65214	(HeLa) helix-loop-helix prot HE47 (E2A); Also: M31523	+
U57342	myelodysplasia/myeloid leukemia factor 2 (MLF2)	−
D85245	TR3beta	+
U39447	placenta copper monamine oxidase	−
U07807	metallothionein IV (MTIV)	+
U97018	echinoderm microtubule-associated prot homolog HuEMAP	−
D87076	Br140/KIAA0239	+
U34252	gamma-aminobutyraldehyde dehydrogenase	−
S72487	Platelet-derived endothelial growth factor 1 (ECGF1)	+
J02963	platelet glycoprot IIb	+
U30255	phosphogluconate dehydrogenase (hPGDH)	+
D38524	5-nucleotidase (NT5C2)	+
U46751	phosphotyrosine independent ligand p62	−
HG1879-	Ras-Like prot Tc10	+
HT1919
L13434	chromosome 3p211 sequence	+
U37012	cleavage and polyadenylation specificity factor	+
HG4662-	Omega Light Chain Ig Lambda Light Chain Related	+
HT5075
M29536	translational initiation factor 2 beta subunit (eIF-2-beta)	−
D21235	HHR23A prot	−
U65093	msg1-related 1 (mrg1)	+
M32011	neutrophil oxidase factor (p67-phox)	+
X04412	plasma gelsolin	−
S80905	PRB2 (PRB2L CON1+) = Con1	+
M60626	N-formylpeptide receptor 1 (FPR1)	+
D83243	NPAT	+
X73478	hPTPA	−
J05243	nonerythroid alpha-spectrin (SPTAN1)	−
S42303	N-cadherin	−
Y09305	prot kinase Dyrk4	−
HG1980-	Tubulin, Beta 2	−
HT2023
L42611	keratin 6 isoform K6e (KRT6E)	+
U66619	SWI/SNF complex 60 KDa subunit (BAF60c)	−
U40282	integrin-linked kinase (ILK)	−
AB004884	PKU-alpha	+
X72841	IEF 7442	−
U13695	homolog of yeast mutL (hPMS1)	+
U67171	selenoprot W (selW)/U67171	−
X97335	kinase A anchor prot	−
U82130	tumor susceptiblity prot (TSG101)	−
Z80780	H2B/h/Z80780	+
U52112	Renin binding protein (RENBP)	+
U14193	TFIIA gamma subunit	−
U66618	SWI/SNF complex 60 KDa subunit (BAF60b)	+
M24461	pulmonary surfactant-associated prot SP-B (SFTP3)	+
U77735	pim-2 protoonco homolog pim-2 h	+
D25216	hypothetical protein/KIAA0014	−
U28369	semaphorin V	−
J04611	lupus p70 (Ku) autoantigen prot	−
X76770	PAP	+
U58970	outer mitochondrial membrane translocase (TOMM34)	−
U78628	leukemia inhibitory factor receptor/U78628	+
Z68274	cosmid L129H7, Huntingtons Disease Region/Z68274	+
X13967	leukaemia inhibitory factor (LIF/HILDA)	+
L37868	POU-domain transcription factor (N-Oct-3); Also: Z11933	−
U35451	heterochromatin prot p25	−
X15880	collagen VI alpha-1 C-terminal globular domain	−
X79780	YPT3	−
D63485	Inhibitor of NFkB kinase epsilon subU. IkBKE/KIAA0151	+
HG3748-	Basic Transcription Factor 44 Kda Subunit	+
HT4018
X80907	phosphatidyl-inositol-3-kinase p85 (PIK3R2)	+
U31930	deoxyuridine nucleotidohydrolase	−
U93049	SLP-76 associated prot	+
M74715	alpha-L-iduronidase (IDUA); Also: M95740	+
D82061	short-chain alcohol dehydrogenase family	+
L10838	SR prot family pre-splicing factor (SRp20)	+
X55448	Glucose 6 phosphate dehydrogenase	−
U82979	Ig-like transcript-3 (LILRB4)	+
M21154	S-adenosylmethionine decarboxylase	+
U51432	nuclear prot Skip	−
X54870	NKG2-D	+
D87440	hypothetical protein/KIAA0252	−
X85116	epb72; Also: U33931 Same Unigene Cluster as M81635	−
Z23090	28 kDa heat shock prot	−
HG2992-	Beta-Hexosaminidase Alpha Polypeptide	+
HT5186
M55593	collagenase type IV (CLG4)	−
X15341	COX VIa-L cytochrome c oxidase liver-specific subunit Via	−
HG4638-	Spliceosomal prot Sap 49	+
HT5050
U59058	beta-A3/A1 crystallin (CYRBA3/A1); Also: M14306	+
HG3255-	Gaba A Receptor Beta 2 Subunit	+
HT3432
X83368	phosphatidylinositol 3 kinase gamma (PIK3CG)	+
L46720	autotaxin-t (atx-t); Also: L35594	−
J03040	SPARC/osteonectin	−
HG3214-	Metallopanstimulin 1	+
HT3391
HG4102-	N-Ethylmaleimide-Sensitive Factor (NSF)	+
HT4372
U79295	clone 23961 sequence	+
M54915	h-pim-1 prot (h-pim-1); Also: M27903, M24779	+
L13848	RNA helicase A (DDX9)	+
M86528	neurotrophin-4 (NT-4)	+
M96843	striated muscle contraction regulatory prot (Id2B)	+
J02883	Colipase (CLPS)	+
HG1602-	Utrophin	+
HT1602
L41559	pterin-4a-carbinolamine dehydratase (PCBD)	−
X01677	glyceraldehyde-3-phosphate dehydrogenase	−
M80899	novel protein desmoyokin (AHNAK)	+
D50915	hypothetical protein/KIAA0125	+
D49728	NAK1 DNA binding prot,	+
U82671	HSP1-A from cosmids from Xq28	+
S45630	alpha B-crystallin = Glioma Rosenthal fiber component	−
AB002318	talin homolog/KIAA0320	+
L42373	prot phosphatase 2A B56-alpha	+
L10284	integral membrane prot calnexin (IP90)	−
M81780	Sphingomyelin phosphodiesterase 1 (SMPD1)	+
M91036	G-gamma globin (HBG2)	+
Z24725	mitogen inducible mig-2	−
D29805	beta-14-galactosyltransferase	+
HG358-	Homeotic prot 7 Notch Group	+
HT358
Z50022	surface glycoprot	−
X99664	prot containing SH3 domain SH3GL3	+
AB002380	leukemia-associated Rho GEF/KIAA0382	−
X63131	My1 (PML); Also: M73778	−
J00129	fibrinogen beta-chain	+
S62539	insulin receptor substrate-1	−
X51956	ENO2 neuron specific (gamma) enolase	−
M22382	mitochondrial matrix prot P1 (nuclear encoded)	−
S68874	EP3 prostanoid receptor EP3-I/D86096_1/X83858/L27490	+
D29954	hypothetical protein/KIAA0056	+
U70735	34 kDa mov34 isologue/U70735	−
X69878	Flt4 transmembrane tyrosine kinase	+
HG36-	PM-Sc1 autoantigen/M58460	−
HT4101
L24774	delta3, delta2-CoA-isomerase; Also: Z25821_rna1, Z25820	−
L04953	Amyloid precursor protein binding APBA1	+
X77548	RFG	+
U18919	chromosome 17q12-21 clone pOV-2	−
S68805	L-arginine: glycine amidinotransferase	−
M62782	insulin-like growth factor binding prot 5 (IGFBP-5)/M65062	−
Z97074	Rab9 effector p40/Z97074	−
AB002315	Hypothetical protein/KIAA0317	+
U22398	Cdk-inhibitor p57KIP2 (KIP2)	−
M23197	differentiation antigen (CD33)	+
U01147	guanine nucleotide regulatory prot (ABR)	−
U51586	siah binding prot 1 (SiahBP1)	−
M83652	complement component properdin; Also: X57748, X70872_rna1	+
X04143	bone gla prot (BGP)	−
M13928	X64467_rna1 and others	−
U15642	transcription factor E2F-5; Also: U31556	+
U18235	ATP-binding cassette prot (ABC2) HFBCD04 clone	+
U84487	CX3C chemokine precursor	−
X95404	non-muscle type cofilin	−
D63160	DNA lectin P35/Ficolin 2 (FCN2)	+
X13255	dopamine beta-hydroxylase type a (EC 114171)	+
M12125	fibroblast muscle-type tropomyosin,	−
X99268	B-HLH DNA binding prot	−
U65533	regulator of nonsense transcript stability (RENT1)/D86988	−
L22342	nuclear phosphoprot	+
U00928	clone CE29 4.1 (CAC)n/(GTG)n repeat-containing	+
M10901	glucocorticoid receptor alpha	+
HG3942-HT4212	Interferon	−
M27161	MHC class I CD8 alpha-chain (Leu-2/T8)	+
D90276	CGM7 nonspecific cross-reacting antigen (NCA)	+
U42359	N33 prot/U42359	−
HG987-	Mac25	−
HT987
L40933	phosphoglucomutase-related prot (PGMRP)	−
M19961	cytochrome c oxidase subunit Vb (coxVb)	−
X58199	adducin 2 beta (ADD2); Also: S81083_1	+
U20582	actin-like peptide (LOC81569)	+
D30655	eukaryotic initiation factor 4All	+
L10910	splicing factor (CC13)	−
M11749	Thy-1 glycoprot	−
D79989	centaurin gamma-1/KIAA0167	+
U12595	tumor necrosis factor type 1 receptor associated prot (TRAP1)	−
L37042	casein kinase I alpha isom (CSNK1A1)	+
X86809	major astrocytic phosphoprot PEA-15	−
M24766	alpha-2 collagen type IV (COL4A2); Also: X05610	−
HG1140-	Collagen, Type Vi, Alpha 2; Also: M34570	−
HT4817
X64624	RDC-1 POU domain containing prot; Also: L20433	+
D28473	T-lymphocyte isoleucyl-tRNA synthetase; Also: U04953	−
M29277	isolate JuSo MUC18 glycoprot/M28882, X68264_rna1	−
HG429-	B-Cell Growth Factor 1	+
HT429
L02840	potassium channel Kv21 (KCNB1)	+
M33308	Vinculin (VCL)	−
M22995	ras-related prot (Krev-1)	+
X99226	FAA prot	−
HG3104-	Serine Protease Met1	+
HT3280
U51010	nicotinamide N-methyltransferase 1 and 5 ing region/U08021	−
U32114	caveolin-2	−
M60750	histone H2B.1 (H2B)/M60750	+
HG3740-	Basic Transcription Factor 2 34 Kda Subunit	+
HT4010
M24398	parathymosin	−
Z11502	annexin A13 (ANXA13)	+
J04080	complement component C1r	−
U47927	isopeptidase T (ISOT)	−
HG1800-	Ribosomal prot S20	+
HT1823
L10405	DNA binding prot surfactant prot B/L10405	−
D17400	6-pyruvoyl-tetrahydropterin synthase	−
J03798	autoantigen small nuclear ribonucleoprot Sm-D	+
X99586	SMT3C prot; Also: U67122, U83117, U61397	+
D49487	obese/Leptin (LEP); Also: U43653	+
D29642	GTPase/KIAA0053	+
HG1155-	Colony-Stimulating Factor 1 Macrophage (CSF1)	+
HT4822
X14046	leukocyte antigen CD37	+
U11690	faciogenital dysplasia (FGD1)	−
U61234	tubulin-folding cofactor C	+
U91932	AP-3 complex sigma 3A subunit (AP3S1)	−
S81083	beta subunit 63 kDa	−
D16593	BDR-2 hippocalcin	−
M22760	nuclear-encoded mitochondrial cytochrome c oxidase Va	−
U71364	serine protase inhibitor (P19)	+
J03805	phosphatase 2A; Also: M60484_rna1	−
L10955	carbonic anhydrase IV; Also: M83670	+
X53416	actin-binding prot (filamin) (ABP-280)	−
D42040	RING3 protein/KIAA9001; Also: X62083, M80613	+
X52221	ERCC2	+
M32334	intercellular adhesion molecule 2 (ICAM-2)	+
X64559	tetranectin	−
M16750	pim-1 oncogene; Also: M27903, M24779, M54915	+
M30269	nidogen	+
M33374	cell adhesion prot (SQM1)	−
M27396	asparagine synthetase; Also: M15798	−
M31627	X box binding prot-1 (XBP-1)	+
X97230	NK receptor, clone library 4M1#6	+
U89012	dentin matrix acidic phosphoprot 1 (DMP1)	+
D83597	RP105	+
M13207	granulocyte-macrophage colony-stimulating factor (CSF1)	−
L04733	kinesin light chain	−
X82240	T cell leukemia/lymphoma 1 (TCL1A)	+
U65406	KCNJ1 (from potassium channel ROM-K1-6)	+
U79263	clone 23760	+
S57212	hMEF2C = myocyte enhancer-binding factor 2; Also: L08895	+
X13461	calmodulin-like prot (CLP); Also: M58026	+
X12447	aldolase A (ALDOA) (EC 41213)	−
M27504	topoisomerase type II (Topo II)/M27504/Also: Z15115	+
X54941	ckshs1 Cks1 prot homolog	−
M28882	MUC18 glycoprot; Also: X68264_rna1	−
X93499	RAB7 prot	+
Z49989	smoothelin	−
U61500	GT334 prot (GT334)	+
U38980	PMS2 related (hPMSR6)	+
Z18954	S100D calcium binding prot	+
U57627	fetal brain oculocerebrorenal syndrome (OCRL1)	−
M64673	heat shock factor 1 (TCF5)	−
U82279	Ig-like transcript 2 (LILRB1)	+
M57609	DNA-binding prot (GLI3)	+
U89335	Notch 4	+
M61733	erythroid membrane protein 41 (EPB41)	+
Y07604	nucleoside-diphosphate kinase	−
M37766	MEM-102 glycoprot	+
D13634	Hypothetical protein/KIAA0009	+
X52142	CTP synthetase (EC 6342)	−
D26018	DNA polymerase delta subunit 3/KIAA0039	−
X98743	RNA helicase (Myc-regulated dead box prot)	+
X75535	PxF prot	−
U27193	prot-tyrosine phosphatase	−
U47686	signal transducer and activator of transcription Stat5B/U48730	+
L43964	(clone F-T03796) STM-2	−
U08316	insulin-stimulated prot kinase 1 (ISPK-1)	+
D50683	TGF-betallR alpha	+
L34355	(clone p4) 50 kD dystrophin-associated glycoprot,	−
L24470	prostanoid FP receptor	+
AC002464	BAC clone RG331P03/AC002464	−
L10678	profilin II	−
X80590	PHKG1	+
U04270	putative potassium channel subunit (KCNH2)	−
K02054	gastrin-releasing peptide	+
M11313	alpha-2-macroglobulin; Also: M36501	−
HG4321-	Ahnak-Related prot	+
HT4591
X15882	collagen VI alpha-2 C-terminal globular domain	−
U50534	BRCA2 region sequence CG003	−
U94586	NADH: ubiquinone oxidoreductase MLRQ subunit	−
M26576	COL4A1 (alpha-1 type IV collagen)	−
U50079	histone deacetylase HD1; Also: D50405	+
L38593	D50402 and others	+
D26067	Hypothetical protein/KIAA0033	+
X13589	aromatase (estrogen synthetase) (CYP19A1)	+
L13689	prot-onco (BMI-1)	−
X80909	alpha NAC nascent polypeptide-associated complex	−
Y11710	extracellular matrix prot collagen type XIV, C-terminus	−
D38550	E2f-3 transcription factor/KIAA0075	+
M65062	insulin-like growth factor binding prot 5 (IGFBP-5)	−
X74330	DNA primase (PRIM1)	+
HG2743-	Caldesmon 1, 4, Non-Muscle; Also: HG2743-HT2843	−
HT2846
X94628	MeCP-2; Also: L37298, Y12643, X89430	−
U29953	pigment epithelium-derived factor	−
D63879	T cell-recognized SART-3/KIAA0156	+
X81003	HCG V	+
X60483	H4/D histone	+
X92896	ITBA2 prot	−
M73548	polyposis locus (DP25)	+
M14058	complement C1r	−
Z27113	RNA polymerase II subunit 144 kD	−
J02923	65-kilodalton phosphoprot (p65)	+
X79568	BDP1 prot-tyrosine-phosphatase	−
J03060	glucocerebrosidase (GCB)	−
X07618	cytochrome P450 db1 variant a; Also: X07619, X16866	+
U55936	SNAP-23	+
U45328	ubiquitin-conjugating enzyme (UBE2I); Also: U31882	+
M17885	acidic ribosomal phosphoprot P0	−
U56402	chromatin structural prot homolog (SUPT5H); Also: Y12790	−
HG3431-	Decorin; Also: HG3431-HT3617	−
HT3616
X78338	Synthetic adenovirus transformed retinal cell line MRP	+
J04621	heparan sulfate proteoglycan (HSPG) core prot end	−
X74801	Cctg chaperonin	−
U28055	hepatocyte growth factor-like prot homolog (D1F15S1A)	−
M62810	mitochondrial TRANSCRIPTION FACTORS 1	−
HG4263-	Nkr-P1a prot	+
HT4533
U52154	G prot-coupled inwardly rectifying potassium channel Kir34	+
U37352	prot phosphatase 2AB alpha 1	+
D50926	Hypothetical protein/KIAA0136	+
X16560	COX VIIc subunit VIIc of cytochrome c oxidase (EC 1931)	−
U18088	3,5-cyclic AMP phosphodiesterase; Also: M37744, S75213	−
L76159	FRG1	−
S90469	cytochrome P450 reductase	−
HG3635-	Zinc Finger prot, Kruppel-Like	+
HT3845
X69433	mitochondrial isocitrate dehydrogenase (NADP+)	−
U09953	ribosomal prot L9	−
X06745	DNA polymerase alpha-subunit (POLA)	−
HG3033-	Spliceosomal prot Sap 62	+
HT3194
D13720	LYK; Also: L10717	+
X60221	H+-ATP synthase subunit b	−
M55905	mitochondrial NAD(P)+ dependent malic enzyme	+
HG4128-	Anion Exchanger 3 Cardiac Isom	+
HT4398
U62325	FE65-like prot (hFE65L)	−
M21186	neutrophil cytochrome b light chain p22	+
U09851	zinc finger prot (ZNF148); Also: L04282	+
D50919	TRIM14 protein/KIAA0129	+
HG3044-	Fibronectin; Also: HG3044-HT2527, X02761	−
HT3742
M14676	src-like kinase (slk)	+
D87673	heat shock transcription factor 4 (HSF4)	+
J04809	Cytosolic adenylate kinase AK1	+
X15183	90-kDa heat-shock prot	−
M95623	PBGD from hydroxymethylbilane synthase	−
U15174	Nip3 (NIP3)	+
Z50115	thimet oligopeptidase (metalloproteinase); Also: U29366	−
AF001548	815A9.1 myosin heavy chain from chromosome 16	−
M30894	T-cell receptor Ti rearranged gamma-chain V-J-C region	+
L10615	beta casein (CSN2); Also: X17070	+
L14922	DNA-binding prot (PO-GA)	+
U27768	RGP4	+
U68485	Box-dependent MYC-interacting prot-1 (BIN1)	+
X14008	lysozyme (EC 3.2.1.17)	+
X82693	Lymphocyte antigen 6 complex, locus D (E48)	+
J05582	Mucin 1 (MUC1); Also: J05581	−
U77665	RNaseP prot p30 (RPP30)	−
L05425	autoantigen	−
U34343	13 kD differentiation-associated protein (DAP13)	−
D63486	hypothetical protein/KIAA0152	−
L32179	arylacetamide deacetylase	−
D13628	angiopoietin 1/KIAA0003	−
U45973	phosphatidylinositol (45)bisphosphate 5-phosphatase homolog	+
X05610	type IV collagen alpha-2 chain	−
M94172	N-type calcium channel alpha-1 subunit (CACNA1B)	+
Y08319	kinesin-2 (KIF2)	+
S82447	GCN5-like 1 = GCN5; Also: D64007	−
U72512	B-cell receptor associated prot (hBAP)/U72512	+
X17648	granulocyte-macrophage colony-stimulating factor receptor	+
L07044	Ca-Calmodulin-dependent prot kinase CAMK	−
L06132	voltage-dependent anion channel isom 1 (VDAC)	−
M95787	22 kDa smooth muscle prot (SM22)	−
U48296	prot tyrosine phosphatase PTPCAAX1 (hPTPCAAX1)	−
M11718	alpha-2 type V collagen	−
U24576	breast tumor autoantigen sequence	−
X77383	cathepsin-O	+
U50939	amyloid precursor prot-binding prot 1	−
U91903	Fritz	−
U57341	neurofilament L (NFL)	+
D83407	ZAKI-4	−
Z83735	hH3/k	+
U70439	silver-stainable prot SSP29; Also: Y07570	−
D13435	phosphatidyl-inositol-glycan class F	+
M67468	Fragile X mental retardation 1 FMR-1; Also: X69962, L19493	+
L32832	alpha fetoprotein enhancer binding protein/D10250	−
X59372	HOX4C a homeobox prot	−
HG1103-	Guanine Nucleotide-Binding prot Ral	+
HT1103
Z80345	SCAD; Also: M26393	−
U23946	putative tumor suppressor (LUCA15)	+
D50810	placental leucine aminopeptidase	+
L35475	olfactory receptor-like	+
U07563	ABL 1b and intron 1b, and putative M8604 Met prot	−
L19779	histone H2A2	+
M28825	thymocyte antigen CD1a	+
D50918	septin 2, 6 (SEPT6)/KIAA0128	+
D13969	Mel-18 prot	−
Z84718	22q11.2-qter DNA contains GSTT1-2 glutathione transferases	−
X53296	IRAP; Also: X64532_rna1, X52015	+
M63262	5-lipoxygenase activating prot (FLAP)	+
HG3546-	Pre- Splicing Factor Sf2p33; Also: M72709, M72709_rna2	+
HT3744
U72342	platelet activating factor acetylhydrolase 45 kDa subunit (LIS1)	−
X51804	PMI a putative receptor prot	−
L42243	IFNAR2 (interferon receptor)	+
U09087	thymopoietin (TMPO); Also: U09088	+
J04617	elongation factor EF-1-alpha; Also: M27364	+
X54871	ras-related prot RAB5B	+
M31520	ribosomal prot S24; Also: HG3214-HT3391	−
U90878	LIM domain prot CLP-36	−
X61373	alternatively spliced tau/X61373	+
L20860	glycoprotein Ib beta (GP1BB)	+
D45371	GS3109 adipose most abundant gene transcript 1 (APM1)	+
X16546	eosinophil derived neurotoxin	+
M14636	liver glycogen phosphorylase	+
X02176	complement component C9; Also: K02766	−
Z37166	BAT1 nuclear RNA helicase (DEAD family)	−
L10844	cellular growth-regulating prot	−
X56692	C-reactive prot	+
L29376	(clone 38-1) MHC class I fragment	+
U67932	cAMP phosphodiesterase (Pde7A2)/U67932; Also: L12052	+
M64595	small G prot (Gx)	+
J02783	thyroid hormone binding prot (p55)	−
D16181	PMP2	+
X72012	endoglin	−
M14123	HERV-K10 neutral protease	−
J03278	MYCL2	−
Y07827	butyrophilin (BTN)/U90552	+
S77812	flt = vascular endothelial growth factor receptor/VEGF receptor	+
D12775	erythrocyte-specific AMP deaminase; Also: U29926_2	+
X95073	translin associated prot X	+
D79999	VPARP vault protein/KIAA0177	+
M68891	GATA-binding prot (GATA2)	+
U05321	X-linked PEST-containing transporter (XPCT)	−
X80818	metabotropic glutamate receptor type 4	+
U20350	G prot-coupled receptor V28	+
M96233	glutathione transferase class mu number 4 (GSTM4)	−
U19495	intercrine-alpha (hIRH); Also: L36034	−
J04101	NAD(P)H: menadione oxidoreductase; Also: M81600	+
L08177	EBV induced G-prot coupled receptor (EBI2)	+
U40490	nicotinamide nucleotide transhydrogenase	+
D13637	toll-like receptor 1 (TLR1)/KIAA0012	+
HG4704-	Glial Growth Factor 2	+
HT5146
U40571	alpha1-syntrophin (SNT A1)	−
L37043	casein kinase I epsilon	−
M28879	granzyme B/CTLA-1 (GZMB)	+
U78190	GTP cyclohydrolase I feedback regulatory prot	+
M61764	gamma-tubulin	−
M81830	somatostatin receptor isom 2 (SSTR2)	+
M83751	arginine-rich prot (ARP)	−
D25218	yeast ribosome biogenesis regulator homolog/KIAA0112	+
L10377	(clone CTG-B37) sequence; Also: D38529, U23851, D31840	−
U80457	TRANSCRIPTION FACTORS SIM2 short form	−
Z50194	PQ-rich prot	+
X51405	carboxypeptidase E (EC 341710)	−
Y08999	Sop2p-like prot	−
M16447	dihydropteridine reductase (hDHPR)	+
L20316	glucagon receptor	+
D78132	Ras homolog enriched in brain (RHEB); Also: Z29677	−
S71129	acetylcholinesterase (ACHE)	+
U79301	clone 23842 sequence	+
D14661	Splicing regulator WTAP protein/KIAA0105	+

[0038]

TABLE 7
Highly discriminatory genes for MS (on no treatment)
vs. Healthy Donors and ALS
		Up (+) or down
Probe sets	Gene Descriptions	(−)
D30037	phosphatidylinositol transfer protein (PITPN)	+
D29675	iNOS	+
Z25884	CIC-1 muscle chloride channel protein (CLCN1)	+
U78095	Placental bikunin (AMBP)	+
U14187	receptor tyrosine kinase ligand LERK-3/Ephrin-A3	+
L34357	GATA-4	+
U79528	SR31747 binding prot 1 (SRBP1); Also: U75283	+
HG3991-HT4261	Cpg-Enriched Dna, Clone E18	+
U18271	thymopoietin (TMPO)	+
HG2415-HT2511	Transcription Factor E2f-2	+
Z16411	phospholipase c; Also: U26425, Z37544 (PLCB3)	−
D26069	Centaurin beta 2 (CENTB2)/KIAA0041	+
D45132	kidney zinc-finger DNA-binding protein PRDM2	+
D87450	parallel sister chromatids drosophila prot-like/KIAA0261	+
M25269	tyrosine kinase (ELK1) onco	+
D38491	Hypothetical protein/KIAA0117	+
X72879	14A2AK DNA sequence	+
HG2825-HT2949	Ret Transforming	+
M13994	bcl-2-alpha; Also: M14745	+
Z15114	protein kinase C gamma (PRKCG)	+
U03398	receptor 4-1BB ligand (TNFSF9)	+
D38449	G protein-coupled receptor (GPR)	+
HG3175-HT3352	Carcinoembryonic Antigen	+
M19650	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
M30818	interferon-induced cellular resistance mediator MxB (MX2)	+
X65977	corticostatin HP-4 precursor (defensin/DEFA4)	+
S68874	EP3 prostanoid receptor EP3-I	+
U57341	neurofilament L (NFL)	+
L05512	histatin 1 (HTN1)	+
X83492	Fas/APO1 (TNFRSF6)	+
D64158	cell differentiation-associated ATP binding prot	+
D30036	phosphatidylinositol transfer protein (PITPN)	+
X80878	R kappa B (NFRKB)	+
U66059	TCRBV1S1A1N1 from germline TCR beta chain	+
U39318	E2 ubiquitin conjugating enzyme UbcH5C (UBCH5C)	+
U59752	Sec7p-like prot	+
L34075	FKBP-rapamycin associated prot (FRAP)	+
HG4108-HT4378	Olfactory Receptor Or17-24	+
X07619	cytochrome P450 db1 variant b; Also: X16866	+
HG3730-HT4000	Tyrosine Kinase Syk; Also: L28824	+
M35416	GTP-binding prot (RALB)	+
M13577	myelin basic prot (MBP)	+
S76617	protein tyrosine kinase (BLK)	+
L36922	Met-ase 1/Granzyme M (GZMM)	+
D49487	obese/Leptin (LEP); Also: U43653	+
D83784	C2 H2-type zinc finger protein/KIAA0198	+
L20860	glycoprotein lb beta (GP1BB)	+
U61500	GT334 prot (GT334)	+
M60626	N-formylpeptide receptor 1 (FPR1)	+
D79993	Hypothetical/KIAA0171/Enthoprotin (ENTH)	+
U22028	cytochrome P450 (CYP2A13)	+
U63717	osteoclast stimulating factor (OSTF1)	+
Z46632	HSPDE4C1 3,5-cyclic AMP phosphodiesterase (PDE4C)	+
L77561	DiGeorge syndrome critical region 11 DGS-D (DGCR11)	+
M34181	testis-specific cAMP-dependent prot kinase (PRKACB)	+
S82362	hRAR-beta 2 = retinoic-acid-receptor beta	+
U50743	NaK-ATPase gamma subunit	+
D26579	transmembrane prot ADAM8	+
U20647	zinc finger prot (ZNF151)	+
HG4094-HT4364	Transcription Factor Lsf-Id; Also: U03494	+
U34301	nonmuscle myosin heavy chain IIB	+
U53347	neutral amino acid transporter B (SLC1A5)	+
HG4115-HT4385	Olfactory Receptor Or17-210	+
U25975	serine kinase (hPAK65)	+
U78575	phosphatidylinositol 4-phosphate 5-kinase alpha PIP5K1A	+
U37431	HOX A1	+
Z26256	L-type calcium channel/Z26256	+
X54871	ras-related prot RAB5B	+
L10717	T cell-specific tyrosine kinase	+
M20778	alpha-3 (VI) collagen; Also: X52022	+
D14661	Splicing regulator WTAP protein/KIAA0105	+
D82344	NBPhox (PHOX2B)	+
D83779	Hypothetical protein/KIAA0195	+
Z47727	RNA polymerase II subunit	+
D89859	zinc finger 5 protein (ZNF5)	+
Z78289	(clone 1D2)/Z78289	+
AB002315	Hypothetical protein/KIAA0317	+
D87969	CMP-sialic acid transporter (SLC35A1)	+
AC002486	BAC clone RG367O17/7p15-p21/AC002486	+
D38524	5-nucleotidase (NT5C2)	+
M28879	granzyme B/CTLA-1 (GZMB)	+
Y09392	WSL-LR, WSL-S1 and WSL-S2 prots; Also: U74611	+
D86967	alpha mannosidase-like protein/KIAA0212	+
X75755	PR264; Also: HG3088-HT3261	+
Z49254	L23-related MRPL23	−
D28364	annexin II (ANXA2)	+
U75272	gastricsin/progastricsin (PGC); Also: J04443	+
L35253	p38 mitogen activated prot (MAP) kinase; Also: L35264	+
D50926	Hypothetical protein/KIAA0136	+
U47635	D13S824E locus	−
U76388	steroidogenic factor 1 (NR5A1)	+
D87076	Br140/KIAA0239	+
L42324	(clone GPCR W) G prot-linked receptor/L42324	+
D16626	Histidine ammonia lyase (HAL)	+
D80004	Hypothetical protein/KIAA0182	+
HG3925-HT4195	SFTPA2D	+
M13699	ceruloplasmin (CP)	+
M90299	glucokinase (GCK)	+
X89267	DNA uroporphyrinogen decarboxylase (UROD)	+
U49835	YKL-39 precursor; Also: U58514, U58515	+
D28416	esterase D (ESD)	+
U15173	Nip2 (NIP2)	+
X78686	Chemokine (C-X-C motif) ligand 5 (CXCL5)	+
Y14140	G protein-encoding beta 3 subunit 1 (GNB3)	+
X60483	H4/D histone	+
M28219	low density lipoprot receptor (FH 10)	+
D85418	phosphatidylinositol-glycan-class C (PIGC)	+
J04162	leukocyte IgG receptor (Fc-gamma-R)	+
D13988	rab GDI	+
U68233	farnesol receptor HRR-1 (HRR-1)	+
K03218	src sarcoma viral oncogene homolog (SRC)	+
S50223	HKR-T1 = Kruppel-like zinc finger prot	+
X94563	dbi/acbp/X94563	+
AF001359	mismatch repair prot (hMLH1)/AF001359	−
U79287	clone 23867/prostate tumor overexpressed 1 (PTOV1)	−
S77583	HERVK10/HUMMTV reverse transcriptase homolog	+
Y00282	ribophorin II (RPN2)	−
S81957	BMP-5 = bone morphogenic prot-5/S81957	+
AD000092	RAD23A homolog	+
D37781	protein-tyrosine phosphatase (PTPRJ); Also: U10886	+
L42611	keratin 6 isoform K6e (KRT6E)	+
M80629	cdc2-like protein kinase 5 (CDC2L5)	+
X13255	dopamine beta-hydroxylase type a (EC 114171)	+
Z12962	homolog to yeast ribosomal prot L41	+
D31883	actin-binding LIM protein 1 (ABLIM1)/KIAA0059	+
U44799	U1-snRNP binding prot homolog; Also: U44798	+
X97303	Ptg-12 prot/X97303	+
U12779	MAP kinase activated protein kinase 2 (MAPKAPK2)	+
M77144	3-b-hydroxysteroid DH/5delta-4delta isomerase	+
X82240	T cell leukemia/lymphoma 1 (TCL1A)	+
HG3104-HT3280	Serine Protease Met1	+
U51561	cosmid N79E2 sequence	+
HG4638-HT5050	Spliceosomal prot Sap 49	+
Z14244	coxVIIb cytochrome c oxidase subunit VIIb (COX7B)	−
M80899	novel protein desmoyokin (AHNAK)	+
X90761	Keratin, hair, acidic, 2 hHa2 (KRTHA2)	+
U91930	AP-3 complex delta subunit (AP3D1)	−
M24461	pulmonary surfactant-associated prot SP-B (SFTP3)	+
U58033	myotubularin related prot 2 (MTMR2)/U58033	+
HG3521-HT3715	Ras-Related prot 1b	+
D87673	heat shock transcription factor 4 (HSF4)	+
U82535	fatty acid amide hydrolase (FAAH)	+
D88613	HGCMa/glial cells missing homolog 1 (GCM1)	+
X13589	aromatase (estrogen synthetase) (CYP19A1)	+
HG3995-HT4265	Cpg-Enriched Dna Clone S19	+
U21049	DD96	+
L13977	prolylcarboxypeptidase (PRCP)	−
HG627-HT5097	Rhesus (Rh) Blood Group Ce-Antigen, 2, Rhvi	+
L76200	guanylate kinase (GUK1)	−
U89896	casein kinase I gamma 2 (CSNK1G2)	+
Y09022	Not56-like protein (NOT56L)	+
X58298	interleukin-6-receptor (IL6R); Also: M20566	+
X12794	v-erbA related ear-2/NR2F6	+
D78361	ornithine decarboxylase antizyme 1 (OAZ1)	+
D63998	golgi alpha-mannosidase II (MAN2A1)	+
M14159	T-cell receptor beta-chain J2.1	+
U79303	clone 23882	+
X16665	HOX2H from the Hox2 locus	+
X99664	prot containing SH3 domain SH3GL3	+
X68836	S-adenosylmethionine synthetase (MAT2A)	+
L27943	cytidine deaminase (CDA)	+
D87685	TFIIS-like PHD finger protein 3/KIAA0244	+
L42563	(clone ISW34) non-gastric HK-ATPase (ATP1AL1)	+
U10886	Protein tyrosine phosphatase (PTPRJ)	+
D42046	DNA replication helicase-like homolog/KIAA0083	+
D28588	Sp2 transcription factor/KIAA0048	+
Y10936	hypothetical prot downstream of DMPK and DMAHP	+
U24685	anti-B cell autoantibody IgM heavy chain V-D-J region	+

[0039]

TABLE 8
Intermediate discriminatory genes for MS (on no treatment)
vs. Healthy Donors and ALS
Y08265	DAN26 prot; Also: U94836	+
L14754	DNA-binding prot (SMBP2)	+
U48405	G prot coupled receptor OGR1	+
M80244	E16	+
D28114	myelin-associated oligodendrocytic basic protein	+
	(MOBP)
Y09443	alkyl-dihydroxyacetonephosphate synthase AGPS	+
HG2715-	Tyrosine Kinase	+
HT2811
U70732	glutamate pyruvate transaminase (GPT)	+
U46461	dishevelled homolog (DVL)	+
AF007111	MDM2-like p53-binding prot (MDMX)	+
X06318	protein kinase C (PKC) type beta I (PRKCB)	+
U07807	metallothionein IV (MTIV)	+
J04809	Cytosolic adenylate kinase AK1	+
Z18954	S100D calcium binding prot	+
U23430	Cholecystokinin type A receptor (CCKAR);	+
	Also: L19315
Z75330	nuclear protein stromal antigen SA-1 (STAG1)	+
HG315-	Beta-1-Glycoprot 11 Pregnancy-Specific (PSG11)	+
HT315
U85767	myeloid progenitor inhibitory factor-1 (MPIF1)	+
X82634	hair keratin acidic 3B (KRTHA3B)	+
D50550	Lethal giant larvae homolog 1 (LLGL1)	+
U09550	oviductal glycoprotein (OVGP1)	+
U09303	T cell leukemia LERK-2 (EPLG2)/Ephrin-B1	+
D28915	hepatitis C-associated protein p44 (IFI44)	+
D38550	E2f-3 transcription factor/KIAA0075	+
D86979	hypothetical protein/KIAA0226	+
X05309	C3b/C4b receptor (CR1) F allotype.	+
U88666	SFRS protein kinase 2 (SRPK2)	+
U79294	clone 23748 phosphatidic acid phosphatase 2B (PPAP2B)	+
HG3517-	Alpha-1-Antitrypsin	+
HT3711
L19593	IL-8 receptor beta (IL8RB)	+
Y07827	butyrophilin (BTN)/U90552	+
S72487	Platelet-derived endothelial growth factor 1 (ECGF1)	+
M31210	Endothelial differentiation protein (EDG-1)	+
X60655	EVX1 homeobox	+
U41068	retinoid X receptor beta (RXRbeta)/collagen alpha2(XI)	+
X83492	Fas/APO1 (TNFRSF6)	+
HG3991-	Cpg-Enriched Dna, Clone E18	+
HT4261
U52154	G prot-coupled inwardly rectifying K+ channel Kir34	+
HG3627-	Calcium Channel Voltage-Gated B-1 Subunit L Type 2	+
HT3836
Y08263	AAD14 prot	+
M16714	MHC class I divergent lymphocyte antigen; clone RS5	+
Z18956	taurine transporter (SLC6A6)	+
U52827	Cri-du-chat region clone NIBB11	+
M29971	6-O-methylguanine-DNA methyltransferase (MGMT)	−
X98534	Vasodilator-stimulated phosphoprotein (VASP); Z46389	+
U59748	desert hedgehog (hDHH)/U59748/	+
X58199	adducin 2 beta (ADD2); Also: S81083_1	+
U27325	thromboxane A2 receptor (TBXA2R); Also: D38081	+
X81892	G protein-couped receptor 64 (GPR64)	+
L04953	Amyloid precursor protein binding APBA1	+
X97324	adipophilin (ADFP)	+
Y08319	kinesin-2 (KIF2)	+
HG3638-	Amyloid Beta (A4) Precursor prot; Also: Y00264	−
HT3849
M10277	cytoplasmic beta-actin; Also: HSAC07/X00351	+
U31903	CREB-RP (CREBL1); Also: U89337_1, X98054	+
D88795	cadherin	+
HG3748-	Basic Transcription Factor 44 Kda Subunit	+
HT4018
X13967	leukaemia inhibitory factor (LIF/HILDA)	+
X52599	beta nerve growth factor	+
Z25535	nuclear pore complex prot hnup153	+
M90391	Interleukin 16 (IL16)	+
Z47038	putative microtubule-associated; prot 1A (MAP1A)	+
U43431	DNA topoisomerase III alpha (TOP3A)	−
M63928	T cell activation antigen (CD27)	+
D31797	CD40 ligand (TNFSF5)	+
L13848	RNA helicase A (DDX9)	+
U72512	B-cell receptor associated prot (hBAP)	+
M89957	B cell receptor complex cell surface glycoprot (IGB)	+
M80335	protein kinase A catalytic subunit (PRKACA)	+
L20941	ferritin heavy chain (FTH1)	−
D30655	eukaryotic initiation factor 4AII	+
X80907	phosphatidyl-inositol-3-kinase p85 (PIK3R2)	+
D85181	fungal sterol-C5-desaturase homolog (SC5DL)	+
U58334	Bcl2 p53 binding prot Bbp/53BP2 (BBP/53BP2)	+
U52112	Renin binding protein (RENBP)	+
D25538	adenylate cyclase 7 (ADCY7)/KIAA0037	+
M98833	ERGB TRANSCRIPTION FACTORS (FLI-1 homolog)	+
Y09943	NGF-inducible PC3 anti-proliferative protein (BTG2)	+
D63160	DNA lectin P35/Ficolin 2 (FCN2)	+
M13955	mesothelial keratin K7 (type II)	+
U03634	P47 LBC onco	+
U05237	fetal Alz-50-reactive clone 1 (FAC1)	+
L41607	beta-16-N-acetylglucosaminyltransferase (IGnT)	+
HG1428-	Globin, Beta; Also: U01317_6	+
HT1428
U10868	aldehyde dehydrogenase ALDH7	+
D42138	Phosphatidylinositol glycan type B (PIG-B)	+
M35999	platelet glycoprot IIIa/Integrin beta 3 (ITGB3)	+
D49490	disulfide isomerase-related protein (PDIR)	+
X06323	MRL3 ribosomal prot L3 homolog	+
Z11502	annexin A13 (ANXA13)	+
X75304	giantin	−
L10955	carbonic anhydrase IV; Also: M83670	+
J05068	transcobalamin I	+
HG4102-	N-Ethylmaleimide-Sensitive Factor (NSF)	+
HT4372
Y00486	adenine phosphoribosyltransferase (aprt)	+
U57057	WD prot IR10	+
X07203	CD20 receptor (S7)	+
X53296	IRAP; Also: X64532_rna1 X52015	+
U58130	bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2)	+
S71129	acetylcholinesterase (ACHE)	+
U37219	cyclophilin-like prot CyP-60	+
D31888	CoREST protein (RCOR)/KIAA0071	+
D25304	Rac/Cdc42 guanine exchange factor/KIAA0006	+
U89336	Notch 4	+
U67932	cAMP phosphodiesterase (Pde7A2)/L12052	+
D63875	TPR-containing SH2-binding phosphoprotein/KIAA0155	+
U10686	MAGE-11 antigen (MAGE11)	+
S75256	HNL = neutrophil lipocalin; Also: X99133	+
U78678	thioredoxin 2 (TXN2)	+
L29376	(clone 38-1) MHC class I fragment	+
X77383	cathepsin-O	+
X52730	phenylethanolamine n-methyltransferase (PNMT)	+
HG2167-	prot Kinase Ht31 Camp-Dependent	+
HT2237
HG3925-	Surfactant prot Sp-A2 Delta/M30838	+
HT4195
X74330	DNA primase (PRIM1)	+
HG3994-	Cpg-Enriched Dna Clone S16	+
HT4264
M95549	sodium/glucose cotransporter-like protein (SLC5A2)	+
S69790	Brush-1 = tumor suppressor	+
U50553	helicase like protein 2 (DDX3)	+
U63541	expressed in HC/HCC livers and MolT-4 cells	+
K02054	gastrin-releasing peptide	+
D50919	TRIM14 protein/KIAA0129	+
D50918	septin 2, 6 (SEPT6)/KIAA0128	+
M91036	G-gamma globin (HBG2)	+
D45371	GS3109 adipose most abundant gene transcript 1 (APM1)	+
D25217	Membrane protein MLC1/KIAA0027	+
D16217	Calpastatin (CAST)	+
U49973	tigger 1 transposable element	+
L07261	alpha adducin (ADD1)	+
HG3635-	Zinc Finger prot, Kruppel-Like	+
HT3845
X53586	integrin alpha 6	+
X13444	CD8 beta-chain glycoprot (CD8 beta1)	+
M29994	alpha-I spectrin (SPNA1); Also: M61877, M61826	+
HG1102-	Ras-Related C3 Botulinum Toxin Substrate (RAC1)	−
HT1102
L39059	TRANSCRIPTION FACTOR SL1 (TAF1C)	−
Y10812	fructose-bisphosphatase	+
D90276	CGM7 nonspecific cross-reacting antigen (NCA)	+
S76992	VAV2 = VAV onco homolog	+
S70348	integrin beta 3 (ITGB3)	+
U70323	ataxin-2 (SCA2)	−
U31248	zinc finger prot (ZNF174)	−
HG1783-	Islet Amyloid Polypeptide; Also: X81832	+
HT1803
X13293	v-myb myeloblastosis viral homolog-like 2 (MYBL2)	−
Y10517	CD108 prot/Y10517	+
X65857	HGMP07E olfactory receptor	+
L15309	zinc finger prot (ZNF141)	+
S74728	antiquitin (ALDH7A1)	−
Z70759	mitochondrial 165 rRNA ()/Z70759	+
U27768	RGP4	+
X90530	ragB prot	+
D85376	DNA thyrotropin-releasing hormone receptor (TRHR)	+
D26067	Hypothetical protein/KIAA0033	+
D86976	minor histocompatibility antigen HA-1/KIAA0223	+
D28423	pre-splicing factor SRp20	+
HG2602-	Succinate Dehydrogenase Flavoprotein (HSSUCCDH)	+
HT2698
U06454	AMP-activated prot kinase (hAMPK)	+
M30607	zinc finger prot Y-linked (ZFY); Also: L10393	−
X02875	(2-5) oligo A synthetase E (1,8 kb RNA)/M11810_2	+
U43030	cardiotrophin-1 (CTF1)	+
L31584	G prot-coupled receptor (EBI1)	+
D83657	calcium-binding prot in amniotic fluid 1 CAAF1	+
	(S100A12)
X99586	SMT3C prot; Also: U67122, U83117, U61397	+
X63097	Rhesus polypeptide RhXIII	+
U82979	Ig-like transcript-3 (LILRB4)	+
D59253	NCBP interacting prot 1	+
HG4114-	Olfactory Receptor Or17-209	+
HT4384
U08815	splicesomal prot (SAP 61)	−
M81637	Grancalcin (GCA)	+
M61855	cytochrome P4502C9 (CYP2C9), clone 25	+
L38935	GT212	+
U25265	MEK5	+
U00928	clone CE29 4.1 (CAC)n/(GTG)n repeat-containing	+
L05628	multidrug resistance-associated prot (MRP)/X78338	+
D13639	G1/S-specific cyclin D2/KIAK0002	+
D50525	TI-227H/D50525	+
S76473	tyrosine kinase receptor trkB (NTRK2); U12140	+
U33920	clone lambda 5 semaphorin 3F (SEMA3F)	+
M25667	neuronal growth prot 43 (GAP-43)	+
U05040	FUSE binding protein (FUBP1)	+
U70862	nuclear factor I/B (NFIB)	+
X12953	ab2 , YPT1-related and member of ras family	+
AF008937	syntaxin-16C	+
HG4272-	Hepatocyte Growth Factor Receptor	+
HT4542
X89430	methyl CpG binding prot 2	+
M27749	Ig-related 14.1 prot	+
D87684	Hypothetical protein/KIAA0317	+
U33921	HSU33921 cDNA	+
X12530	B lymphocyte antigen CD20 (B1, Bp35); Also: X07203	+
S50017	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
U71364	serine protase inhibitor (P19)	+
M27691	transactivator prot (CREB)	+
Z37166	BAT1 nuclear RNA helicase (DEAD family)	−
X54816	alpha-1-microglobulin-bikunin (AMBP)	+

[0040]

TABLE 9
Least discriminatory genes for MS (on no treatment)
vs. Healthy Donors and ALS
M16279	MIC2	−
M14123	HERV-K10 neutral protease	−
U66618	SWI/SNF complex 60 KDa subunit (BAF60b)	+
U37408	C-terminal binding protein 1 (CTBP1)	−
X05196	aldolase C	+
U73304	CB1 cannabinoid receptor (CNR1).	+
L32831	G prot-coupled receptor (GPR3); Also: U18550	+
D87073	zinc finger protein znf142/KIAA0236	+
Z50194	PQ-rich prot	+
U38276	semaphorin III family homolog (SEMA3F)	−
S76756	4R-MAP2 = microtubule-associated prot 2 4R isoform	+
HG1862-	Calmodulin Type I	+
HT1897
L06175	P5-1	+
U91932	AP-3 complex sigma 3A subunit (AP3S1)	−
Z84721	cosmid GG1 from 16p13.3 Contains alpha & zeta globin	+
M61733	erythroid membrane protein 41 (EPB41)	+
D86043	SHPS-1/PTPNS1 tyrosine phosphatase; Also: U06701	−
M65290	Interleukin 12p40 (IL12p40/IL12B)	+
J05016	prot disulfide isomerase related prot (ERp72)	+
J03798	autoantigen small nuclear ribonucleoprot Sm-D	+
HG4128-	Anion Exchanger 3 Cardiac Isom	+
HT4398
X95808	prot encoded by DXS6673E/AB002383	+
L40395	(clone S20iii15)	+
K02574	purine nucleoside phosphorylase (PNP)	+
M25809	endomembrane proton pump subunit	+
X06389	synaptophysin (p38)	+
D13370	APEX nuclease (APEX1)	+
V00565	preproinsulin; Also: M10039	+
U49837	LIM prot MLP (CSRP3)	+
L75847	zinc finger prot 45 (ZNF45)	+
U09087	thymopoietin (TMPO); Also: U09088	+
U04806	U03858 and others	+
M27093	alpha-keto acid dehydrogenase transacylase	+
HG2479-	Helix-Loop-Helix prot Sef2-1d; Also: M74719	+
HT2575
X13930	CYP2A4 P-450 IIA4 prot	+
D42108	phospholipase C-like 1 (PLCL1)	+
M12759	Ig J chain (IGJ)	+
J03764	Plasminogen activator inhibitor 1	+
L06499	ribosomal prot L37a (RPL37A)	+
HG1595-	Heterogeneous Nuclear Ribonucleoprot I	+
HT4788
L13329	iduronate-2-sulfatase (IDS)	+
X67683	keratin 4 (KRT4)	+
HG1733-	Moloney Murine Sarcoma Viral Oncogene Homolog	+
HT1748
M27543	guanine nucleotide-binding prot (Gi) alpha subunit	−
D63506	unc-18 homolog	+
U73477	acidic nuclear phosphoprot pp32; Also: X75090	+
D87078	Translational repressor Pumilio/KIAA0235	+
HG3546-	Pre-Splicing Factor Sf2p33	+
HT3744
U33052	lipid-activated, prot kinase PRK2; Also: S75548	+
X57809	rearranged Ig lambda light chain	+
U68536	zinc finger protein 45 (ZNF45); Also KOX17	+
X53683	LAG-1	+
L17327	pre-T/NK cell associated prot (3B3)	+
X66867	MAX	+
U07919	aldehyde dehydrogenase 6	+
S78798	1-phosphatidylinositol-4-phosphate 5-kinase isoform C	+
M64269	mast cell chymase; Also: M69137	−
S80905	PRB2 (PRB2L CON1+) = Con1	+
X52011	MYF6 encoding a muscle determination factor	+
X82693	Lymphocyte antigen 6 complex, locus D (E48)	+
S72503	HRK1 = inward rectifier potassium channel/U07364	+
S81083	beta subunit 63 kDa	−
M15395	leukocyte adhesion prot (LFA-1/Mac-1/p150,95)	+
X64878	oxytocin receptor	−
D87735	ribosomal prot L14	+
D43947	Hypothetical protein/KIAA0100	+
X90846	mixed lineage kinase 2 (MAP3K10)	+
X66142	rod cGMP phosphodiesterase 6b (PDE6B); Also: S41458	+
HG2992-	Beta-Hexosaminidase Alpha Polypeptide	+
HT5186
HG64-	NF-Kappa B-Binding protein (KBP1)	−
HT64
U09953	ribosomal prot L9	−
D38503	PMS8 (yeast PMS1 homolog	+
D87445	Hypothetical protein/KIAA0256	+
U82671	HSP1-A from cosmids from Xq28	+
Z83336	hH2B/d	+
M86406	skeletal muscle alpha 2 actinin (ACTN20	−
D87845	platelet-activating factor acetylhydrolase 2	+
X76061	p130 retinoblastoma-like 2 (RBL2)	+
M32886	sorcin CP-22 (SRI)	−
Z49194	oct-binding factor	+
M81830	somatostatin receptor isom 2 (SSTR2)	+
K01911	neuropeptide Y (NPY)	+
U79261	clone 23959 (MAPK8IP2); Also: U62317	+
D87432	solute carrier family 7/KIAA0245	+
U55054	K-Cl cotransporter (hKCC1)	+
J00129	fibrinogen beta-chain	+
U49395	ionotropic ATP receptor P2X5a	+
Z80787	Histone H4	+
D50402	Natural resistance associated macrophate prot1	+
	(NRAMP1)
M74091	cyclin C	+
D80006	Hypothetical protein/KIAA0184	+
X17622	HBK2 potassium channel prot	+
Z80780	H2B/h/Z80780	+
L10338	sodium channel beta-1 subunit (SCN1B)/U12194/L16242	+
X80026	B-cam	+
HG4321-	Ahnak-Related prot	+
HT4591
S82297	beta 2-microglobulin	+
HG3033-	Spliceosomal prot Sap 62	+
HT3194
U68488	5-hydroxytryptamine7 receptor isoform d	+
AF002224	E6-AP ubiquitin prot ligase 3A (UBE3A)	+
X84194	acylphosphatase erythrocyte (CT) isoenzyme	+
M76424	carbonic anhydrase VII (CA VII)	+
D30758	Centaurin beta 1 (CENTB1)/KIAA0050	+
HG907-	Mg44	+
HT907
X83490	Fas/Apo-1/X83490; Also: X83493, X63717	+
M25079	sickle cell beta-globin	+
U82279	Ig-like transcript 2 (LILRB1)	+
U66559	anaplastic lymphoma kinase receptor	−
HG3989-	Cpg-Enriched Dna Clone E14	+
HT4259
U20428	SNC19 sequence	+
D50692	c-myc binding prot	+
U18919	chromosome 17q12-21 clone pOV-2	−
AB002559	hunc18b2	+
S77576	ERV9 reverse transcriptase homolog/S77576	+
X12447	aldolase A (ALDOA) (EC 41213)	−
D78367	K12 keratin	+
U22233	methylthioadenosine phosphorylase (MTAP)	+
X97160	TFE3 transcription factor from TFE3	+
D67029	SEC14L	+
U15197	histo-blood group ABO prot	+
M80478	platelet glycoprot IX precursor (gpIX)	+
AF005775	caspase-like apoptosis regulatory prot 2 (CLARP)	+
Y10514	CD152 prot (CTLA4); Also: Y10508	−
U51432	nuclear prot Skip	−
M81758	voltage-dependent sodium channel SKM1 (SCN4A)	+
U14973	ribosomal prot S29	+
U68494	hbc647 sequence	+
U00238	glutamine PRPP amidotransferase (GPAT)	−
U04270	putative potassium channel subunit (KCNH2)	−
M16441	Lymphotoxin	+
D87434	Hypothetical protein/KIAA0247	+
D13644	tre oncogene homolog/KIAA0019	+
U20938	Lymphocyte dihydropyrimidine dehydrogenase (DPYD)	+
M94172	N-type calcium channel alpha-1 subunit (CACNA1B)	+
M63959	alpha-2-macroglobulin receptor-associated prot	−
L08069	heat shock prot E coli DnaJ homolog	+
V00594	metallothionein 2A (MT2A); Also: J00271	−
U09002	N-methyl-D-aspartate receptor subunit 2A (GRIN2A)	+
U01317	beta-globin thalassemia	+
X80692	ERK3	−
AJ001421	Rer1	+
U41740	trans-Golgi p230 (GOLGA4)	−
U20760	extracellular calcium-sensing receptor	+
M60830	Ecotropic viral integration site 2B (EVI2B)	+
X60487	H4/h H4 histone	+
L15326	endoperoxide synthase type II	+
Y13618	DFFRY prot	+
D16350	SA	+
X95735	zyxin 2	−
HG4460-	Ig Heavy Chain Vdjc Regions	+
HT4729
HG884-	Oncogene E6-Ap, Papillomavirus; Also: U84404	−
HT884
M33308	Vinculin (VCL)	−
M27394	B-lymphocyte cell-surface antigen B1 (CD20)	+
U40714	tyrosyl-tRNA synthetase (YARS)	+
U30245	myelomonocytic specific prot (MNDA)/U30245	+
X80909	alpha NAC nascent polypeptide-associated complex	−
U08096	peripheral myelin prot-22 (PMP22)/U08096	−
M37435	macrophage-specific colony-stimulating factor (CSF-1)	+
U23435	Abl interactor 2 (Abi-2); Also: X95632, X95677	+
HG3412-	Blue Cone Photoreceptor Pigment; Also: M13299	+
HT3593
D56495	Reg-related sequence derived peptide-2 (REGL)	+
M54995	connective tissue activation peptide III	+
D29956	ubiquitin specific protease 8/KIAA0055	+
L42572	p87/89 mitochondrial inner membrane protein (IMMT)	−
U83410	CUL-2 (cul-2)	+
K02766	complement component C9	−
HG4662-	Omega Light Chain Ig Lambda Light Chain Related	+
HT5075
L49173	OCP2/L49173	+
L35035	ribose 5-phosphate isomerase (RPI)	+
U15642	transcription factor E2F-5; Also: U31556	+
AF007551	Bet1p homolog (hbet1)	+
X59711	CAAT-box DNA binding prot subunit A	+
S81243	CHN = steroid/thyroid orphan receptor homolog/U12767	+
X69636	sequence (15q11-13)	+
U36759	pre-T cell receptor alpha-type chain precursor (PTCRA)	+
U22398	Cdk-inhibitor p57KIP2 (KIP2)	−
U79252	clone 23679	+
X60188	ERK1 prot serine/threonine kinase	−
D11327	protein tyrosine phosphatase (PTPN7); Also: M64322	+
Z48923	BMPR-II	+
D21852	hypothetical protein/KIAA0029	+
X57809	rearranged Ig lambda light chain; Also: S42404	+
D80007	RRP5 protein homolog/KIAA0185	+
X71125	glutamine cyclotransferase (QPCT)	+
M31642	hypoxanthine phosphoribosyltransferase (HPRT)	−
U96769	chondroadherin	+
D83174	collagen binding prot 2 (SERPINH1); Also: X61598	−
M30838	pulmonary surfactant apoprot (PSAP)	+
M60746	histone H3.1 (H1F3)	+
U74382	telomeric repeat DNA-binding prot (PIN2);	+
	Also: U40705
X16983	integrin alpha-4 subunit VLA4 (ITGA4)	+
U00115	zinc-finger prot (bcl-6)	−
D16181	PMP2	+
X15875	cAMP response element binding prot CREBP1 (ATF2)	−
HG1103-	Guanine Nucleotide-Binding prot Ral	+
HT1103
X59812	CYP 27 vitamin D3 25-hydroxylase	+
D49357	S-adenosylmethionine synthetase	+
L24470	prostanoid FP receptor	+
L11701	phospholipase D; Also: L11702	+
L19183	MAC30	−
U33822	tax1-binding prot TXBP181, MAD1-like 1 (MAD1L1)	+
Y07829	RING prot	+
U90905	clone 23574 sequence	+
M22995	ras-related prot (Krev-1)	+
U41371	spliceosome associated prot (SAP 145)	−
U79272	clone 23720 sequence	+
M13929	c-myc-P64/HG3523-HT4900/HG3523-HT4899/L00058	+
Z19554	vimentin (VIM); Also: M18895_2	−
M30269	nidogen	+
AB000449	VRK1	+
X07618	cytochrome P450 db1 variant a/X07619/X16866/M33189	+
D79986	bcl-2-associated transcription factor/KIAA0164	+
U76010	putative zinc transporter ZnT-3 (ZnT-3)	+
Z38026	FALL-39 peptide antibiotic	−
U79255	X11 prot	−
X79865	Mrp17/Mitochondrial ribosomal L12 (MRPL12)	−
M81750	myeloid cell nuclear differentiation antigen	+
U73377	p66shc (SHC)	−
U43965	ankyrin G119 (ANK3)	+
U03688	dioxin-inducible cytochrome P450 (CYP1B1)	+
U47050	putative calcium influx channel (htrp3)	−
M19645	78 kdalton glucose-regulated prot (GRP78)	−
X95404	non-muscle type cofilin	−
D50640	phosphodiesterase 3B (PDE3B)	+
M62831	TRANSCRIPTION FACTORS ETR101	+
U06863	follistatin-related protein precursor (FSTL1)	+
L11672	Kruppel related zinc finger prot (HTF10)	+
M80397	DNA polymerase delta catalytic subunit; Also: M81735	−
D10656	Sarcoma virus homolog (CRK)	+
D86959	hSLK serine threonine kinase/KIAA0204	+
J02982	glycophorin B	+
X81333	PPH beta subunit prot	+
X76105	Death-associated protein (DAP1)	−
M92642	alpha-1 type XVI collagen (COL16A1),	+
U38175	HuR RNA binding prot (HuR)	−
HG3636-	Myosin, Heavy Polypeptide 9, Non-Muscle	+
HT3846
L37378	guanylyl cyclase (RetGC-2)	−
X82200	Staf50	+
Y08409	spot14	+
D38583	calgizzarin	+
D78514	ubiquitin-conjugating enzyme	+
M31627	X box binding prot-1 (XBP-1)	+
U81556	hypothetical prot A4	+
U07550	Chaperonin 10 (HSPE1)	−
X52943	ATF-a TRANSCRIPTION FACTORS	−
X95654	SCP1 prot	+
L16842	ubiquinol cytochrome-c reductase core l prot (UQCRC1)	−
M26004	CR2/CD21/C3d/Epstein-Barr virus receptor/J03565	+
D28476	thyroid hormone receptor interactor 12/KIAA0045	+
X80590	PHKG1	+
X59842	PBX2; Also: U89336_2, D28769_1, X80700_rna1	−
Y07847	RRP22 prot	+
U15306	cysteine-rich sequence-specific DNA-binding prot NFX1	+
L39874	deoxycytidylate deaminase	+
D16154	cytochrome P-450c11/D16154	+
X98253	ZNF183/X98253	+
M59941	GM-CSF receptor beta chain (CSF2RB)	+
L10615	beta casein (CSN2); Also: X17070	+
X64728	CHML	+
S41458	rod cGMP phosphodiesterase 6B (PDE6B)	+
X87176	17-beta-hydroxysteroid dehydrogenase	+
HG3884-	Homeotic protein HPX42	−
HT4154
U15174	Nip3 (NIP3)	+
D64015	T-cluster binding protein/D64015	+
U80040	aconitase nuclear encoded mitochondrial prot	−
U19878	transmembrane prot	+
D83018	nel-related prot 2	+
M22538	mitochondrial NADH-ubiquinone reductase	−
	24 Kd subunit
U37055	hepatocyte growth factor-like prot/L11924/M74178	−
M75715	TB3-1; Also: X81625	−
U02566	receptor tyrosine kinase TIF; Also: U18934	−
X74142	HBF-1 TRANSCRIPTION FACTORS	+
M16750	pim-1 oncogene; Also: M27903, M24779, M54915	+
U73799	dynactin/U73799	+
V01516	cytoskeletal keratin (type II) from foreskin	+
J02960	unknown prot/M15169	+
U34380	prot tyrosine kinase TEC and TXK (txk)/D29767	+
S78432	transmembrane 4 prot/S78432	−
U70439	silver-stainable prot SSP29; Also: Y07570	−
U90916	clone 23815 sequence, lFN-inducible	+
M99438	transducin-like enhancer prot (TLE3)	+
X98248	Sortilin (SORT1)	+
L11931	cytosolic serine hydroxymethyltransferase (SHMT)	+
U68485	Box-dependent MYC-interacting prot-1 (BIN1)	+
X14975	CD1 R2 MHC-related antigen	+
S75578	4-aminobutyrate aminotransferase (ABAT)	−
D28235	PTGS2 prostaglandin endoperoxide synthase-2/U04636	+
X99656	prot containing SH3 domain SH3GL1	+
U08854	UDP glucuronosyltransferase UGT2B15/U06641	+
D14889	small GTP-binding protein S10 (RAB33A)	+
M31899	DNA repair helicase (ERCC3)	−
M75099	Rapamycin and FK506-binding protein FKBP13	−
Z68193	Opsin 1 (OPN1LW)	+
U01212	olfactory marker prot (OMP)	+
X74331	DNA primase (subunit p58)	+
M91029	AMP deaminase (AMPD2)	+
U63295	seven in absentia homolog	−
U58970	outer mitochondrial membrane translocase (TOMM34)	−
L08010	reg homolog	+
M67468	Fragile X mental retardation 1 FMR-1/X69962	+
M13829	putative raf related prot (pks/a-raf); Also: U01337	+
U16811	Bak; Also: U23765	−
U34877	biliverdin-IXalpha reductase	−
D16593	BDR-2 hippocalcin	+
L19871	activating TRANSCRIPTION FACTORS 3 (ATF3)	−
D86964	dedicator of cytokinesis 1 homolog protein/KIAA0209	+
U80017	Survival motor neuron protein (SMN)	−
M81780	Sphingomyelin phosphodiesterase 1 (SMPD1)	+
D42044	hypothetical protein/KIAA0090	+
Y07701	aminopeptidase	+
D29954	hypothetical protein/KIAA0056	+
X61373	alternatively spliced tau/X61373	+
K01884	Blym-1 transforming	+
L37792	syntaxin 1A	+
X65488	Heterogeneous nuclear ribonucleoprotein U (HNRPU)	+
J05243	nonerythroid alpha-spectrin (SPTAN1)	−
D63485	Inhibitor of NFkB kinase epsilon subU.	+
	IkBKE/KIAA0151
M60750	histone H2B.1 (H2B)/M60750	+
D13897	peptide YY precursor	+
X04470	antileukoprotease (ALP) from cervix uterus/X04503	+
U65581	ribosomal prot L3-like	+
U35113	metastasis-associated mta1	−
X62822	beta-galactoside alpha-26-sialyltransferase	+
D50477	membrane-type matrix metalloproteinase 3/D83646	+
U59736	TRANSCRIPTION FACTORS (NFATcb)	+
X07173	second prot of inter-alpha-trypsin inhibitor complex	+
X52638	6-phosphofructo-2-kinase/fructose-26-bisphosphatase	+
Z46632	HSPDE4C1 3,5-cyclic AMP phosphodiesterase (PDE4C)	+
D38024	facioscapulohumeral muscular dystrophy (FSHD)	+
D87435	golgi-specific brefeldin A resistance factor/KIAA0248	+
L20859	leukemia virus receptor 1 GLVR1 (SLC20A1)	+
AF006087	Arp2/3 prot complex subunit p20-Arc (ARC20)	+
U83239	CC chemokine STCP-1; Also: U83171	+
D13435	phosphatidyl-inositol-glycan class F	+
M37815	CD28	+
X03342	ribosomal prot L32	−
D88797	cadherin	+
U85430	TRANSCRIPTION FACTORS NFATx4	+
U96131	HPV16 E1 prot binding prot/U96131	+
X62078	GM2 activator protein (GM2A)	−
U62389	cytosolic NADP-dependent isocitrate dehydrogenase	+
U02680	protein tyrosine kinase 9 (PTK9)	−
U89922	lymphotoxin beta isoform variant/L11016_rna1, L11015	+
Y08999	Sop2p-like prot	−
D83032	nuclear prot NP220	+
U66077	DAZ, 3 UTR	+
D86960	Hypothetical protein/KIAA0205	+
U86136	telomerase-associated prot TP-1	+
U51010	nicotinamide N-methyltransferase/U08021	−
X65644	MBP-2 MHC binding prot 2	+
M18391	tyrosine kinase receptor (eph); Also: Z27409	+
L20298	TRANSCRIPTION FACTORS (CBFB)	+
U62801	protease M	+
M93405	methylmalonate semialdehyde dehydrogenase	+
	(ALDH6A1)
D26561	ORF E7 from papillomavirus 5b genome	+
U37352	prot phosphatase 2AB alpha 1	+
D00760	proteasome subunit HC3	+
U88726	symplekin/U88726	+
Y09615	mitochondrial transcription termination factor (MTERF)	+
M65214	(HeLa) helix-loop-helix prot HE47 (E2A); Also: M31523	+
X15393	motilin	+
X59373	HOX4D a homeobox prot	+
M29696	interleukin-7 receptor (IL-7)	+
X07834	Manganese superoxide dismutase SOD2	+
U43203	thyroid transcription factor 1 (TTF-1); Also: U33749	+
U01923	BTK region clone ftp-3	+
X97444	transmembrane prot Tmp21-Ilex./X97444	+
D49489	disulfide isomerase-related prot P5	+
M54915	h-pim-1 prot (h-pim-1); Also: M27903, M24779	+
X05345	histidyl-tRNA synthetase (HRS)	−
U94585	requiem homolog (hsReq)	+
D88799	cadherin	+
S81916	phosphoglycerate kinase	+
J04088	DNA topoisomerase II (top2)	+
D83597	RP105	+
X97230	NK receptor, clone library 4M1#6	+
HG1155-	Colony-Stimulating Factor 1 Macrophage (CSF1)	+
HT4822
U31342	nucleobindin	+
M13207	granulocyte-macrophage colony-stimulating factor CSF1	−
U24704	antisecretory factor-1 (PSMD4)	−
U14391	myosin-IC	−
L10405	DNA binding prot surfactant prot B/L10405	−
U21943	organic anion transporting polypeptide (OATP)	+
U58087	Hs-cul-1	+
M21188	insulin-degrading enzyme (IDE)	−
D42040	RING3 protein/KIAA9001; Also: X62083, M80613	+
HG1602-	Utrophin	+
HT1602
X61072	T cell receptor, clone IGRA17	+
M60298	erythrocyte membrane prot band 42 (EPB42)	+
U79280	clone 23575	+
HG3141-	Nadh-Ubiquinone Oxidoreductase, 39 Kda Subunit	+
HT3317
U52077	mariner1 transposase/U52077; Also: U80776	−
L22454	nuclear respiratory factor-1 (NRF-1)	+
Y00503	keratin 19	+
HG2139-	Beta-1-Glycoprot 1, Pregnancy-Specific/M25384	+
HT2208
M58026	NB-1	−
HG2320-	Integrin Beta 3 Subunit	+
HT2416
S69265	neuron-specific RNA recognition motifs; Also: L26405	+
M93284	pancreatic lipase related prot 2 (PLRP2)	+
M75110	HK-ATPase beta subunit	+
M19283	cytoskeletal gamma-actin	−
L46720	autotaxin-t (atx-t); Also: L35594	−
H46990	CYT P450 IIE1 homolog	+
X76059	YRRM1	−
AC002086	PAC clone DJ525N14/Xq23	+
M17885	acidic ribosomal phosphoprot P0	−
U64863	hPD-1 (hPD-1)	−
M80333	m5 muscarinic acetylcholine receptor	+
U40705	telomeric repeat binding factor (TRF1)	−
Y09980	HOXD3	−
D49818	fructose 6phosphate 2kinase/fructose2 6bisphosphatase	−
HG4263-	Nkr-P1a prot	+
HT4533
M29277	isolate JuSo MUC18 glycoprot (3′ variant)	−
Y10615	CYRN2/Y10615	+
D83785	mam1 mastermind homolog/KIAA0200	+
J02611	apolipoprot D	+
D87119	cancellous bone osteoblast	+
U07857	18 kDa Alu RNA binding prot	−
U94332	osteoprotegerin (OPG)	−
D42053	Site-1 protease transcription factor/KIAA0091	+
J05272	IMP dehydrogenase type 1	+
M29610	glycophorin E	+
U71300	snRNA activating prot complex 50 kD subunit (SNAP50)	+
M98776	keratin 1	+
L22650	early lymphoid activation prot (EPAG)	+
M23533	alpha 2 adrenergic receptor	+
L14922	DNA-binding prot (PO-GA)	+
X95073	translin associated prot X	+
X66087	a-myb	+
U79267	clone 23840	−
X85786	DNA binding regulatory factor	+
M57423	phosphoribosylpyrophosphate synthetase subunit III	+
HG3214-	Metallopanstimulin 1	+
HT3391
Z29064	AF-1p	+
D86425	osteoblast osteonidogen	−
X95152	brca2	+
J04617	elongation factor EF-1-alpha; Also: M27364	+
X95826	ART4/X95826	+
X52221	ERCC2	+
U40215	synapsin IIb	+
HG4167-	Nuclear Factor 1 A Type	+
HT4437
M29540	carcinoembryonic antigen (CEA)	+
X77166	kunitz-type protease inhibitor HKIB9	+
D49728	NAK1 DNA binding prot,	+
X98258	M-phase phosphoprot mpp9	+
HG3123-	Homeotic prot Gbx2	+
HT3299
M91463	glucose transporter (GLUT4)	+
HG1140-	Collagen, Type Vi, Alpha 2; Also: M34570	−
HT4817
X54150	Fc receptor	−
X90857	(−14) containing globin regulatory element (CGTHBA)	−
U67611	Mouse transaldolase/U67611	+
M34175	beta adaptin	+
J02883	Colipase (CLPS)	+
U34976	gamma-sarcoglycan (SGCG)	−
Z80788	H4/I	+
U89335	Notch 4	+
X06268	pro-alpha 1 (II) collagen	+
X94910	ERp31 prot	+
U80811	Lysophosphatidic acid receptor homolog (EDG2)	−
U52153	inwardly rectifying potassium channel Kir32	−
U14577	microtubule-associated prot 1A (MAP1A)/U38291_rnal	+
M34376	beta-microseminoprot (MSP); Also: X57928	+
U68723	checkpoint suppressor 1	−
L11708	17 beta hydroxysteroid dehydrogenase type 2	+
U58034	myotubularin related prot 3 (MTMR3)/U58034	−
Z22551	kinectin	−
D50915	hypothetical protein/KIAA0125	+
U57352	sodium channel 1 (hBNaC1)	+
M62324	modulator recognition factor I (MRF-1)	−

[0041]

TABLE 10
Highly discriminatory genes for MS (regardless of treatment with Avonex or
not) vs. Healthy Donors and ALS
Probe sets	Gene Descriptions	Up (+) or down (−)
Z16411	phospholipase c; Also: U26425, Z37544 (PLCB3)	−
U78095	Placental bikunin (AMBP)	+
L34075	FKBP-rapamycin associated prot (FRAP)	+
D79993	Hypothetical/KIAA0171/Enthoprotin (ENTH)	+
L42324	(clone GPCR W) G prot-linked receptor/L42324	+
D29675	iNOS	+
U79528	SR31747 binding prot 1 (SRBP1); Also: U75283	+
U39318	E2 ubiquitin conjugating enzyme UbcH5C (UBCH5C)	+
M19650	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
Y09392	WSL-LR, WSL-S1 and WSL-S2 prots; Also: U74611	+
HG3991-HT4261	Cpg-Enriched Dna, Clone E18	+
HG2415-HT2511	Transcription Factor E2f-2	+
M14159	T-cell receptor beta-chain J2.1	−
D30037	phosphatidylinositol transfer protein (PITPN)	+
U63717	osteoclast stimulating factor (OSTF1)	+
HG3730-HT4000	Tyrosine Kinase Syk; Also: L28824	+
U89896	casein kinase l gamma 2 (CSNK1G2)	+
D16626	Histidine ammonia lyase (HAL)	+
D86967	alpha mannosidase-like protein/KIAA0212	+
Z26256	L-type calcium channel/Z26256	+
L34357	GATA-4	+
Y00282	ribophorin II (RPN2)	−
D83784	C2 H2-type zinc finger protein/KIAA0198	+
U66059	TCRBV1S1A1N1 from germline T-cell receptor beta chain	+
HG3175-HT3352	Carcinoembryonic Antigen	+
HG3521-HT3715	Ras-Related prot 1b	+
M90299	glucokinase (GCK)	+
M25269	tyrosine kinase (ELK1) onco	+
U14187	receptor tyrosine kinase ligand LERK-3/Ephrin-A3	+
D26069	Centaurin beta 2 (CENTB2)/KIAA0041	+
X72879	14A2AK DNA sequence	+
D13988	rab GDl	+
U34301	nonmuscle myosin heavy chain IIBU34301	+
Z49254	L23-related MRPL23	−
Z46632	HSPDE4C1 3,5-cyclic AMP phosphodiesterase (PDE4C)	+
M80335	protein kinase A catalytic subunit (PRKACA)	+
X65977	corticostatin HP-4 precursor (defensin/DEFA4)	+
U53347	neutral amino acid transporter B (SLC1A5)	+
X83492	Fas/APO1 (TNFRSF6)	+
HG4108-HT4378	Olfactory Receptor Or17-24	+
X58298	interleukin-6-receptor (IL6R); Also: M20566	+
X07619	cytochrome P450 db1 variant b; Also: X16866	+
D87450	parallel sister chromatids drosophila protein-like/KIAA0261	+
U44799	U1-snRNP binding prot homolog; Also: U44798	+
Z15114	protein kinase C gamma (PRKCG)	+
U22028	cytochrome P450 (CYP2A13)	+
HG1862-HT1897	Calmodulin Type I	+
U03398	receptor 4-1BB ligand (TNFSF9)	+
D38491	Hypothetical protein/KIAA0117	+
U79287	clone 23867/prostate tumor overexpressed 1 (PTOV1)	−
D78361	ornithine decarboxylase antizyme 1 (OAZ1)	+
D87969	CMP-sialic acid transporter (SLC35A1)	+
L05512	histatin 1 (HTN1)	+
HG2825-HT2949	Ret Transforming	+
U59752	Sec7p-like prot	+
U78575	phosphatidylinositol 4-phosphate 5-kinase alpha PIP5K1A	+
D26579	transmembrane prot ADAM8	+
D25304	Rac/Cdc42 guanine exchange factor/KIAA0006	+
M35416	GTP-binding prot (RALB)	+
U18271	thymopoietin (TMPO); Also: U09087, U09088	+
S74728	antiquitin (ALDH7A1)	−
L36922	Met-ase 1/Granzyme M (GZMM)	+
L77561	DiGeorge syndrome critical region 11 DGS-D (DGCR11)	+
X94563	dbi/acbp/X94563	+
D45132	kidney zinc-finger DNA-binding protein PRDM2	+
M34181	testis-specific cAMP-dependent prot kinase (PRKACB)	+
X57809	rearranged Ig lambda light chain	+
U70732	glutamate pyruvate transaminase (GPT)	+
U47635	D13S824E locus	−
M29971	6-O-methylguanine-DNA methyltransferase (MGMT)	−
L27943	cytidine deaminase (CDA)	+
U31248	zinc finger prot (ZNF174)	−
HG315-HT315	Beta-1-Glycoprot 11 Pregnancy-Specific (PSG11)	+
HG4115-HT4385	Olfactory Receptor Or17-210	+
HG2715-HT2811	Tyrosine kinase	+
Z25884	CIC-1 muscle chloride channel protein (CLCN1)	+
L76200	guanylate kinase (GUK1)	−
K03218	src sarcoma viral oncogene homolog (SRC)	+
HG2167-HT2237	prot Kinase Ht31 Camp-Dependent	+
U46461	dishevelled homolog (DVL)	+
Z12962	homolog to yeast ribosomal prot L41	+
U76388	steroidogenic factor 1 (NR5A1)	+
M13994	bcl-2-alpha; Also: M14745	+
U49835	YKL-39 precursor; Also: U58514, U58515	+
Y08265	DAN26 prot; Also: U94836	+
D30036	phosphatidylinositol transfer protein (PITPN)	+
M86406	skeletal muscle alpha 2 actinin (ACTN20	−
J04162	leukocyte IgG receptor (Fc-gamma-R)	+
U50743	NaK-ATPase gamma subunit	+
AC002486	BAC clone RG367O17/7p15-p21/AC002486	+
D64158	cell differentiation-associated ATP binding prot	+
D86976	KIAA0223	+
U91930	AP-3 complex delta subunit (AP3D1)	−
M20778	alpha-3 (VI) collagen; Also: X52022	+
M27749	Ig-related 14.1 prot	+
D28423	pre-splicing factor SRp20	+
D86043	SHPS-1/PTPNS1 tyrosine phosphatase; Also: U06701	−
M10277	cytoplasmic beta-actin; Also: HSAC07/X00351	+
HG3995-HT4265	Cpg-Enriched Dna Clone S19	+
X68836	S-adenosylmethionine synthetase (MAT2A)	+
U20647	zinc finger prot (ZNF151)	+
Z14244	coxVIIb cytochrome c oxidase subunit VIIb (COX7B)	−
D28416	esterase D (ESD)	+
D31797	CD40 ligand (TNFSF5)	+
U79303	clone 23882	+
D29833	salivary proline rich peptide P-B	+
S82297	beta 2-microglobulin	+
AD000092	RAD23A homolog	+
D86979	hypothetical protein/KIAA0226	+
M13577	myelin basic prot (MBP)	+
AF008937	syntaxin-16C	+
S76992	VAV2 = VAV onco homolog	+
X12794	v-erbA related ear-2/NR2F6	+
X05309	C3b/C4b receptor (CR1) F allotype.	+
D28588	Sp2 transcription factor/KIAA0048	+
HG3627-HT3836	Calcium Channel Voltage-Gated Beta 1 Subunit L Type 2	+
X99586	SMT3C prot; Also: U67122, U83117, U61397	+
M19645	78 kdalton glucose-regulated prot (GRP78)	−
Y09022	Not56-like protein (NOT56L)	+
X66867	MAX	+
X75755	PR264; Also: HG3088-HT3261 Same Uni Cluster as M90104	+
X52599	beta nerve growth factor	+
U68536	zinc finger protein 45 (ZNF45); Also KOX17	+
U09550	oviductal glycoprotein (OVGP1)	+
K01884	Blym-1 transforming	+
D50640	phosphodiesterase 3B (PDE3B)	+
M29696	interleukin-7 receptor (IL-7)	+
X02875	(2-5) oligo A synthetase E (1,8 kb RNA); Also: M11810_2	+
U75272	gastricsin/progastricsin (PGC); Also: J04443	+
HG3991-HT4261	Cpg-Enriched Dna, Clone E18	+
X75304	giantin	−
M63959	alpha-2-macroglobulin receptor-associated prot	−
Z70759	mitochondrial 16S rRNA ()/Z70759	+
Y08409	spot14	+
D49487	obese/Leptin (LEP); Also: U43653	+
X13444	CD8 beta-chain glycoprot (CD8 beta1)	+
S82362	hRAR- beta 2 = retinoic-acid-receptor beta/S82362/M62303	+
X52943	ATF-a TRANSCRIPTION FACTORS	−
D31883	actin-binding LIM protein 1 (ABLIM1)/KIAA0059	+
D87735	ribosomal prot L14	+
X15875	cAMP response element binding prot CREBP1 (ATF2)	−
D86964	dedicator of cytokinesis 1 homolog protein/KIAA0209	+
U41371	spliceosome associated prot (SAP 145)	−
Y09443	alkyl-dihydroxyacetonephosphate synthase AGPS	+
L39059	TRANSCRIPTION FACTOR SL1 (TAF1C)	−
U03634	P47 LBC onco	+
L14754	DNA-binding prot (SMBP2)	+
D37781	protein-tyrosine phosphatase (PTPRJ); Also: U10886	+
M62831	TRANSCRIPTION FACTORS ETR101	+
U48405	G prot coupled receptor OGR1	+
M16279	MIC2	−
M13699	ceruloplasmin (CP)	+
U73477	acidic nuclear phosphoprot pp32; Also: X75090	+
U15197	histo-blood group ABO prot	+
Z18954	S100D calcium binding prot	+
X99664	prot containing SH3 domain SH3GL3	+
U73377	p66shc (SHC)	−
D87434	Hypothetical protein/KIAA0247	+
D11327	protein tyrosine phosphatase (PTPN7); Also: M64322	+
D87445	Hypothetical protein/KIAA0256	+
X82200	Staf50	+
Y09943	NGF-inducible PC3 anti-proliferative protein (BTG2)	+
L08069	heat shock prot E coli DnaJ homolog	+
L13848	RNA helicase A (DDX9)	+

[0042]

TABLE 11
Intermediate discriminatory genes for MS (regardless of treatment with Avonex
or not) vs. Healthy Donors and ALS
M81750	myeloid cell nuclear differentiation antigen	+
D83018	nel-related prot 2	+
M28219	low density lipoprot receptor (FH 10)	+
M81637	Grancalcin (GCA)	+
D25538	adenylate cyclase 7 (ADCY7)/KIAA0037	+
D87673	heat shock transcription factor 4 (HSF4)	+
X98534	Vasodilator-stimulated phosphoprotein (VASP); Z46389	+
L31584	G prot-coupled receptor (EBI1)	+
L17327	pre-T/NK cell associated prot (3B3)	+
X90761	Keratin, hair, acidic, 2 hHa2 (KRTHA2)	+
L29376	(clone 38-1) MHC class I fragment	+
M98833	ERGB TRANSCRIPTION FACTORS (FLI-1 homolog)	+
U50553	helicase like protein 2 (DDX3)	+
U20428	SNC19 sequence	+
M75099	Rapamycin and FK506-binding protein FKBP13	−
L10717	T cell-specific tyrosine kinase	+
X80692	ERK3	−
L35253	P38 mitogen activated prot (MAP) kinase; Also: L35264	+
L19593	IL-8 receptor beta (IL8RB)	+
Y00486	adenine phosphoribosyltransferase (aprt)	+
D38524	5 -nucleotidase (NT5C2)	+
M90391	Interleukin 16 (IL16)	+
M32886	sorcin CP-22 (SRI)	−
U09303	T cell leukemia LERK-2 (EPLG2)/Ephrin-B1	+
L15309	zinc finger prot (ZNF141)	+
L06499	ribosomal prot L37a (RPL37A)	+
D13639	G1/S-specific cyclin D2/KIAK0002	+
L42563	(clone ISW34) non-gastric HK-ATPase (ATP1AL1)	+
U52112	Renin binding protein (RENBP)	+
L20859	leukemia virus receptor 1 GLVR1 (SLC20A1)	+
L38935	GT212	+
M13955	mesothelial keratin K7 (type II)	+
Z47727	RNA polymerase II subunit	+
U10886	Protein tyrosine phosphatase (PTPRJ)	+
D30655	eukaryotic initiation factor 4AII	+
X60188	ERK1 prot serine/threonine kinase	−
D80006	Hypothetical protein/KIAA0184	+
X89267	DNA uroporphyrinogen decarboxylase (UROD)	+
Z38026	FALL-39 peptide antibiotic	−
U78678	thioredoxin 2 (TXN2)	+
M15395	leukocyte adhesion prot (LFA-1/Mac-1/p150,95 family)	+
M60626	N-formylpeptide receptor 1 (FPR1)	+
S81083	beta subunit 63 kDa	−
S77583	HERVK10/HUMMTV reverse transcriptase homolog/S77583	+
U25975	serine kinase (hPAK65)	+
HG3994-HT4264	Cpg-Enriched Dna Clone S16	+
HG627-HT5097	Rhesus (Rh) Blood Group Ce-Antigen, 2, Rhvi; Also: X63097	+
U52827	Cri-du-chat region clone NIBB11	+
M60830	Ecotropic viral integration site 2B (EVI2B)	+
U61500	GT334 prot (GT334)	+
U43431	DNA topoisomerase III alpha (TOP3A)	−
M31210	Endothelial differentiation protein (EDG-1)	+
U51432	nuclear prot Skip	−
U27325	thromboxane A2 receptor (TBXA2R); Also: D38081	+
X97303	Ptg-12 prot/X97303	+
D28364	annexin II (ANXA2)	+
D43947	Hypothetical protein/KIAA0100	+
D89859	zinc finger 5 protein (ZNF5)	+
HG3517-HT3711	Alpha-1-Antitrypsin	+
U37055	hepatocyte growth factor-like prot; Also: L11924, M74178	−
L10955	carbonic anhydrase IV; Also: M83670	+
D42046	DNA replication helicase-like homolog/KIAA0083	+
S72503	HRK1 = inward rectifier potassium channel; Also: U07364	+
D83920	uterus ficolin-1	+
M64269	mast cell chymase; Also: M69137	−
U66618	SWI/SNF complex 60 KDa subunit (BAF60b)	+
M24461	pulmonary surfactant-associated prot SP-B (SFTP3)	+
D80004	Hypothetical protein/KIAA0182	+
U41068	retinoid X receptor beta (RXRbeta)/collagen alpha2(XI)	+
D83657	calcium-binding prot in amniotic fluid 1 CAAF1 (S100A12)	+
X53586	integrin alpha 6	+
K02054	gastrin-releasing peptide	+
X94910	ERp31 prot	+
U24685	anti-B cell autoantibody lgM heavy chain variable V-D-J region	+
U89336	Notch 4	+
S68874	EP3 prostanoid receptor EP3-l; Also: D86096_1,	+
HG1140-HT4817	Collagen, Type Vi, Alpha 2; Also: M34570	−
U68233	farnesol receptor HRR-1 (HRR-1)	+
X95735	zyxin 2	−
D83779	Hypothetical protein/KIAA0195	+
D83174	collagen binding prot 2 (SERPINH1); Also: X61598	−
M62324	modulator recognition factor I (MRF-1)	−
L04953	Amyloid precursor protein binding APBA1	+
M80899	novel protein desmoyokin (AHNAK)	+
U90911	clone 23652 sequence	−
Y09980	HOXD3	−
Z18956	taurine transporter (SLC6A6)	+
D50926	Hypothetical protein/KIAA0136	+
U51561	cosmid N79E2 sequence	+
D86965	Hypothetical protein/KIAA0210	+
HG4638-HT5050	Spliceosomal prot Sap 49	+
L16842	ubiquinol cytochrome-c reductase core I prot (UQCRC1)	−
U27768	RGP4	+
AF002224	E6-AP ubiquitin prot ligase 3A (UBE3A)	+
AF007111	MDM2-like p53-binding prot (MDMX)	+
U41740	trans-Golgi p230 (GOLGA4)	−
U70862	nuclear factor I/B (NFIB)	+
D88613	HGCMa/glial cells missing homolog 1 (GCM1)	+
U82979	Ig-like transcript-3 (LILRB4)	+
HG4321-HT4591	Ahnak-Related prot	+
U49395	ionotropic ATP receptor P2X5a	+
D25217	Membrane protein MLC1/KIAA0027	+
U82535	fatty acid amide hydrolase (FAAH)	+
L42611	keratin 6 isoform K6e (KRT6E)	+
HG4094-HT4364	Transcription Factor Lsf-ld; Also: U03494	+
M65290	Interleukin 12p40 (IL12p40/IL12B)	+
M12759	Ig J chain (IGJ)	+
HG4662-HT5075	Omega Light Chain Ig Lambda Light Chain Related	+
D28114	myelin-associated oligodendrocytic basic protein (MOBP)	+
M81758	voltage-dependent sodium channel SKM1 (SCN4A)	+
X89101	Fas/APO1 (TNFRSF6)	+
U09851	zinc finger prot (ZNF148); Also: L04282	+
U33921	HSU33921 cDNA	+
D30758	Centaurin beta 1 (CENTB1)/KIAA0050	+
S75578	4-aminobutyrate aminotransferase (ABAT)	−
D26067	Hypothetical protein/KIAA0033	+
D63875	TPR-containing SH2-binding phosphoprotein/KIAA0155	+
M30269	nidogen	+
Y08319	kinesin-2 (KIF2)	+
U33920	clone lambda 5 semaphorin 3F (SEMA3F)	+
Z37166	BAT1 nuclear RNA helicase (DEAD family)	−
Z11502	annexin A13 (ANXA13)	+
L40395	(clone S20iii15)	+
Y07701	aminopeptidase	+
Y10514	CD152 prot (CTLA4); Also: Y10508	−
L14922	DNA-binding prot (PO-GA)	+
HG4272-HT4542	Hepatocyte Growth Factor Receptor	+
U82671	HSP1-A from cosmids from Xq28	+
X82240	T cell leukemia/lymphoma 1 (TCL1A)	+
U05237	fetal Alz-50-reactive clone 1 (FAC1)	+
AF006087	Arp2/3 prot complex subunit p20-Arc (ARC20)	+
J04617	elongation factor EF-1-alpha; Also: M27364	+
U72512	B-cell receptor associated prot (hBAP)//U72512	+
U37219	cyclophilin-like prot CyP-60	+
HG3214-HT3391	Metallopanstimulin 1	+
X53296	IRAP; Also: X64532_rna1, X52015	+
X13255	dopamine beta-hydroxylase type a (EC 114171)	+
U34380	prot tyrosine kinase TEC and TXK; Also: D29767	+
U58033	myotubularin related prot 2 (MTMR2)/U58033	+
AB002315	Hypothetical protein/KIAA0317	+
U52077	mariner1 transposase/U52077; Also: U80776	−
X77383	cathepsin-O	+
J04809	Cytosolic adenylate kinase AK1	+
U89012	dentin matrix acidic phosphoprot 1 (DMP1)	+
U57341	neurofilament L (NFL)	+
X74330	DNA primase (PRIM1)	+
Z47038	microtubule-associated prot 1A (MAP1A)/Z47038/U38291	+
L20860	glycoprotein Ib beta (GP1BB)	+
U37431	HOX A1	+
U15173	Nip2 (NIP2)	+
X90846	mixed lineage kinase 2 (MAP3K10)	+
Z50194	PQ-rich prot	+
U89922	lymphotoxin beta isoform variant; Also: L11016_rna1, L11015	+
D87684	UBX domain-containing 2 protein/KIAA0242	+
HG4258-HT4528	Kinase Inhibitor P27kip1 Cyclin-Dependent	+
M31642	hypoxanthine phosphoribosyltransferase (HPRT)	−
HG2992-HT5186	Beta-Hexosaminidase Alpha Polypeptide	+
J03798	autoantigen small nuclear ribonucleoprot Sm-D	+
X12953	ab2 , YPT1-related and member of ras family	+
HG4128-HT4398	Anion Exchanger 3 Cardiac Isom	+
Y10517	CD108 prot/Y10517	+
S81957	BMP-5=bone morphogenic prot-5/S81957	+
X13589	aromatase (estrogen synthetase) (CYP19A1)	+
X16665	HOX2H from the Hox2 locus	+
X57809	rearranged Ig lambda light chain; Also: S42404	+
S72487	Platelet-derived endothelial growth factor 1 (ECGF1)	+
D42040	RING3 protein/KIAA9001; Also: X62083, M80613	+
D87078	Translational repressor Pumilio/KIAA0235	+
Z80780	H2B/h/Z80780	+
X58199	adducin 2 beta (ADD2); Also: S81083_1	+
U33822	tax1-binding prot TXBP181, MAD1-like 1 (MAD1L1)	+
D63160	DNA lectin P35/Ficolin 2 (FCN2)	+
U06454	AMP-activated prot kinase (hAMPK)	+
Y10936	hypothetical prot downstream of DMPK and DMAHP	+
HG3748-HT4018	Basic Transcription Factor 44 Kda Subunit	+
U07919	aldehyde dehydrogenase 6	+
U40705	telomeric repeat binding factor (TRF1)	−
U31930	deoxyuridine nucleotidohydrolase	−
S78798	1-phosphatidylinositol-4-phosphate 5-kinase isoform C/U14957	+
M95623	hydroxymethylbilane synthase	−
U55206	gamma-glutamyl hydrolase (hGH)	−
AB002559	hunc18b2	+
X07203	CD20 receptor (S7)	+
D10495	protein kinase C delta-type (PRKCD)	+
D42138	Phosphatidylinositol glycan type B (PIG-B)	+
S80905	PRB2 (PRB2L CON1+)=Con1; Also Similar To: U22312	+
X52011	MYF6 encoding a muscle determination factor	+
U12779	MAP kinase activated protein kinase 2 (MAPKAPK2)	+
M31899	DNA repair helicase (ERCC3)	−
X69141	squalene synthase	−
L42572	p87/89 mitochondrial inner membrane protein (IMMT)	−
M55621	N-acetylglucosaminyltransferase I (GIcNAc-TI)	+
HG884-HT884	Oncogene E6-Ap, Papillomavirus; Also: U84404	−
Z35093	SURF-1	−
D16593	BDR-2 hippocalcin	+
X66142	rod cGMP phosphodiesterase 6b (PDE6B); Also: S41458	+
D38583	calgizzarin	+
L13329	iduronate-2-sulfatase (IDS)	+
X54871	ras-related prot RAB5B	+
D82344	NBPhox (PHOX2B)	+
U49973	tigger 1 transposable element	+
X80907	phosphatidyl-inositol-3-kinase p85 (PIK3R2)	+
L13434	chromosome 3p211 sequence	+
D50919	TRIM14 protein/KIAA0129	+
U10686	MAGE-11 antigen (MAGE11)	+
U62389	cytosolic NADP-dependent isocitrate dehydrogenase/U62389	+
J00129	fibrinogen beta-chain	+
M31523	transcription factor (E2A)	−
M89957	B cell receptor complex cell surface glycoprot (IGB)	+
U43030	cardiotrophin-1 (CTF1)	+
X05345	histidyl-tRNA synthetase (HRS)	−
U15642	transcription factor E2F-5; Also: U31556	+
U38175	HuR RNA binding prot (HuR)	−
J02611	apolipoprot D	+
HG3033-HT3194	Spliceosomal prot Sap 62	+
HG627-HT5098	Rhesus (Rh) Blood Group Ce-Antigenl, 3, Rhviii; Also: X63097	−
D86960	Hypothetical protein/KIAA0205	+
M13207	granulocyte-macrophage colony-stimulating factor (CSF1)	−
J04101	NAD(P)H: menadione oxidoreductase; Also: M81600	+
HG3104-HT3280	Serine Protease Met1	+
HG3546-HT3744	Pre-Splicing Factor Sf2p33; Also: HG3546-HT3746, M72709	+
HG417-HT417	Cathepsin B; Also: L22569	−
D59253	NCBP interacting prot 1	+
HG4114-HT4384	Olfactory Receptor Or17-209	+
X56741	rab8	+
U58034	myotubularin related prot 3 (MTMR3)/U58034	−
X89430	methyl CpG binding prot 2	+
L24470	prostanoid FP receptor	+
D38449	G protein-coupled receptor (GPR)	+
U77735	pim-2 protoonco homolog pim-2h	+
U07550	Chaperonin 10 (HSPE1)	−
U57094	small GTP-binding prot	+
D87119	cancellous bone osteoblast	+
X60655	EVX1 homeobox	+
X90857	(−14) containing globin regulatory element (CGTHBA)	−
U21049	DD96	+
X63422	delta-subunit of mitochondrial F1F0 ATP-synthase (clone #1)	−
D87076	Br140/KIAA0239	+
U50079	histone deacetylase HD1; Also: D50405	+
L10838	SR prot family pre-splicing factor (SRp20)	+
X87176	17-beta-hydroxysteroid dehydrogenase	+
Z78289	(clone 1D2)/Z78289	+
U80040	aconitase nuclear encoded mitochondrial prot	−
X76105	Death-associated protein (DAP1)	−
D85418	phosphatidylinositol-glycan-class C (PIGC)	+
X17648	granulocyte-macrophage colony-stimulating factor receptor	+
X65488	Heterogeneous nuclear ribonucleoprotein U (HNRPU)	+
Z97074	Rab9 effector p40/Z97074	−
M29994	alpha-I spectrin (SPNA1); Also: M61877, M61826	+
U22398	Cdk-inhibitor p57KIP2 (KIP2)	−
M14123	HERV-K10 neutral protease	−
X59871	TCF-1 T cell factor 1	+
M77349	transforming growth factor-beta induced product (BIGH3)	−
M25809	endomembrane proton pump subunit	+
U28369	semaphorin V	−
HG3597-HT3800	Major Histocompatibility Complex, Class I X12432	+
AF001359	mismatch repair prot (hMLH1)/AF001359	−
D14661	Splicing regulator WTAP protein/KIAA0105	+
M58285	membrane-associated prot (HEM-1)	+
M58583	precerebellin and cerebellin	−
M80397	DNA polymerase delta catalytic subunit; Also: M81735	−
X63679	TRAMP prot	+
X72964	caltractin	−
U49188	placenta (Diff33)	+
X57398	pM5 prot	−
X76061	p130 retinoblastoma-like 2 (RBL2)	+
M26901	renin; Also: L00073	+
U34976	gamma-sarcoglycan (SGCG)	−
U31903	CREB-RP (CREBL1); Also: U89337_1, X98054	+
S90469	cytochrome P450 reductase	−
D90276	CGM7 nonspecific cross-reacting antigen (NCA)	+
S81243	CHN=steroid/thyroid orphan receptor homolog; Also: U12767	+
HG2602-HT2698	Succinate Dehydrogenase Flavoprotein (HSSUCCDH)	+
M22995	ras-related prot (Krev-1)	+
X01630	argininosuccinate synthetase	−
D83243	NPAT	+
U20938	Lymphocyte dihydropyrimidine dehydrogenase (DPYD)	+
J05243	nonerythroid alpha-spectrin (SPTAN1)	−
M34175	beta adaptin	+
X67235	proline rich homeobox (Prh) prot; Also: L16499	+
U05040	FUSE binding protein (FUBP1)	+
D82061	short-chain alcohol dehydrogenase family	+
U91932	AP-3 complex sigma 3A subunit (AP3S1)	−
L32832	alpha fetoprotein enhancer binding protein/D10250	−
U37352	prot phosphatase 2AB alpha 1	+
J03764	Plasminogen activator inhibitor 1	+
D86971	Hypothetical protein/KIAA0217	+
D29805	beta-14-galactosyltransferase	+
X79353	XAP-4 GDP-dissociation inhibitor (GDI1)	−
U57057	WD prot IR10	+
M16750	pim-1 oncogene; Also: M27903, M24779, M54915	+
U51903	RasGAP-related prot (IQGAP2)	+
M54995	connective tissue activation peptide III	+
U83410	CUL-2 (cul-2)	+
U15174	Nip3 (NIP3)	+
L19183	MAC30	−
X96506	NC2 alpha subunit; Also: U41843	+
M33308	Vinculin (VCL)	−
HG3635-HT3845	Zinc Finger prot, Kruppel-Like	+
Z48042	encoding GPI-anchored prot p137	+
HG1879-HT1919	Ras-Like prot Tc10	+
M73548	polyposis locus (DP25)	+
X06389	synaptophysin (p38)	+
U70439	silver-stainable prot SSP29; Also: Y07570	−
D67029	SEC14L	+
U82279	Ig-like transcript 2 (LILRB1)	+
HG3925-HT4195	Surfactant prot Sp-A2 Delta; Also: M30838, M68519_rna1	+
U61234	tubulin-folding cofactor C	+
J02963	platelet glycoprot IIb	+
D82345	NB thymosin beta	−
L10615	beta casein (CSN2); Also: X17070	+
D17532	RCK	+
D87436	Lipin 2/KIAA0249	+
X13967	leukaemia inhibitory factor (LIF/HILDA)	+
M91036	G-gamma globin (HBG2)	+
D63506	unc-18 homolog	+
M61733	erythroid membrane protein 41 (EPB41)	+
HG4102-HT4372	N-Ethylmaleimide-Sensitive Factor (NSF)	+
X07173	second prot of inter-alpha-trypsin inhibitor complex	+
U14391	myosin-IC	−
D88795	cadherin	+
M21154	S-adenosylmethionine decarboxylase	+
D16217	Calpastatin (CAST)	+
M91029	AMP deaminase (AMPD2)	+
J04444	cytochrome c-1 (CYC1)	−
X16983	integrin alpha-4 subunit VLA4 (ITGA4)	+
D29642	GTPase/KIAA0053	+
D42108	phospholipase C-like 1 (PLCL1)	+
M19045	lysozyme	+
U69546	RNA binding prot ETR3	+
U24704	antisecretory factor-1 (PSMD4)	−
X86809	major astrocytic phosphoprot PEA-15	−
M13929	c-myc-P64; Also: HG3523-HT4900, HG3523-HT4899, L00058	+
X16546	eosinophil derived neurotoxin	+
U48296	prot tyrosine phosphatase PTPCAAX1 (hPTPCAAX1)	−
Z48923	BMPR-II	+
Y10055	phosphoinositide 3-kinase	+
L06175	P5-1	+
M27504	topoisomerase type II (Topo II)/M27504/Also: Z15115	+
U23946	putative tumor suppressor (LUCA15)	+
X80818	metabotropic glutamate receptor type 4	+
U80628	thymidine kinase 2 isom B (TK2) alternatively spliced	−
U14973	ribosomal prot S29	+
M38258	retinoic acid receptor gamma 1	+
D83597	RP105	+
M81830	somatostatin receptor isom 2 (SSTR2)	+
Z37976	latent transming growth factor-beta binding prot (LTBP-2)	−

[0043]

TABLE 12
Least discriminatory genes for MS (regardless of treatment
with Avonex or not) vs. Healthy Donors and ALS
L33881	prot kinase C iota isom	+
L14778	calmodulin-dependent prot phosphatase PPP3CA	+
D45371	GS3109 adipose most abundant gene transcript 1 (APM1)	+
X53683	LAG-1	+
D87442	Nicastrin/KIAA0253	+
X52730	phenylethanolamine n-methyltransferase (PNMT)	+
M95549	sodium/glucose cotransporter-like protein (SLC5A2)	+
AF005775	caspase-like apoptosis regulatory prot 2 (CLARP)	+
Z69043	translocon-associated prot delta subunit precursor (SSR4)	−
X65857	HGMP07E olfactory receptor	+
U09953	ribosomal prot L9	−
X76648	glutaredoxin	+
U20760	extracellular calcium-sensing receptor	+
M22324	aminopeptidase N	+
Z19554	vimentin (VIM); Also: M18895_2	−
AJ001421	Rer1	+
U00928	clone CE29 4.1 (CAC)n/(GTG)n repeat-containing	+
M77144	3-b-hydroxysteroid dehydrogenase/5-delta-4-delta isomerase	+
S69265	neuron-specific RNA recognition motifs; Also: L26405	+
U55054	K-Cl cotransporter (hKCC1)	+
M92642	alpha-1 type XVI collagen (COL16A1),	+
U47686	signal transducer and activator of transcription Stat5B/U48730	+
HG1471-HT3923	Transcription Factor Oct-1a/1b; Also: X13403	−
L06845	cysteinyl-tRNA synthetase	+
D63998	golgi alpha-mannosidase II (MAN2A1)	+
AF002700	TGF-beta related neurotrophic factor receptor 2 (TRNR2)	+
Y13618	DFFRY prot	+
M19283	cytoskeletal gamma-actin	−
X13930	CYP2A4 P-450 IIA4 prot	+
U07857	18 kDa Alu RNA binding prot	−
D86957	Septin-like protein/KIAA0202	−
HG907-HT907	Mg44	+
X16316	vav oncogene	+
M57609	DNA-binding prot (GLI3)	+
U58032	myotubularin related prot 1 (MTMR1)/U58032	+
U68485	Box-dependent MYC-interacting prot-1 (BIN1)	+
U82130	tumor susceptiblity prot (TSG101)	−
X95404	non-muscle type cofilin	−
M87507	interleukin-1 beta convertase (IL1BCE); Also: U13697	+
HG3405-HT3586	Zinc Finger prot Hzf3	+
X01677	glyceraldehyde-3-phosphate dehydrogenase	−
U07563	ABL and putative M8604 Met prot (M8604 Met)	−
D63879	T cell-recognized SART-3/KIAA0156	+
L07261	alpha adducin (ADD1)	+
HG2479-HT2575	Helix-Loop-Helix prot Sef2-1d; Also: M74719	+
HG3925-HT4195	SFTPA2D	+
X17622	HBK2 potassium channel prot	+
HG3884-HT4154	Homeotic protein HPX42	−
U04270	putative potassium channel subunit (KCNH2)	−
Y00285	insulin-like growth factor II receptor; Also: J03528	−
X99479	NK receptor, clone 12.11C-Also Similar To: X93596, L76672	−
HG1602-HT1602	Utrophin	+
U67171	selenoprot W (selW)/U67171	−
L20941	ferritin heavy chain (FTH1)	−
U34877	biliverdin-IXalpha reductase	−
U79255	X11 prot	−
D49490	disulfide isomerase-related protein (PDIR)	+
Y07827	butyrophilin (BTN)/U90552	+
X82693	Lymphocyte antigen 6 complex, locus D (E48)	+
L20815	S protein/corneodesmosin (CDSN)	+
U56102	adhesion molecule DNAM-1	+
U15306	cysteine-rich sequence-specific DNA-binding prot NFX1	+
X79683	Z68155 and others	−
D31888	CoREST protein (RCOR)/KIAA0071	+
M37721	peptidylglycine alpha-amidating monooxygenase	−
D38024	facioscapulohumeral muscular dystrophy (FSHD)	+
D26561	ORF E7 from papillomavirus 5b genome	+
D56495	Reg-related sequence derived peptide-2 (REGL)	+
D63485	Inhibitor of NFkB kinase epsilon subU. lkBKE/KIAA0151	+
Y14140	G protein-encoding beta 3 subunit 1 (GNB3)	+
L20298	TRANSCRIPTION FACTORS (CBFB)	+
U46025	translation initiation factor elF-3 p110 subunit	−
D49728	NAK1 DNA binding prot,	+
AB002365	Hypothetical protein/KIAA0367	−
HG1733-HT1748	Moloney Murine Sarcoma Viral Oncogene Homolog	+
M54915	h-pim-1 prot (h-pim-1); Also: M27903, M24779	+
U23435	Abl interactor 2 (Abi-2); Also: X95632, X95677	+
X17567	snRNP prot B; Also: J04564	−
D50525	TI-227H/D50525	+
D50683	TGF-betaIIR alpha	+
U41804	putative T1/ST2 receptor binding prot precursor	−
U71364	serine protase inhibitor (P19)	+
X71125	glutamine cyclotransferase (QPCT)	+
D21235	HHR23A prot	−
U35113	metastasis-associated mta1	−
L42373	prot phosphatase 2A B56-alpha	+
M30818	interferon-induced cellular resistance mediator MxB (MX2)	+
X61373	alternatively spliced tau/X61373	+
U46751	phosphotyrosine independent ligand p62	−
Z18951	caveolin	−
M93221	macrophage mannose receptor (MRC1)	−
M63838	interferon-gamma induced prot (IFI 16); Also: S75433	+
X62654	ME491/CD63 antigen	−
K02574	purine nucleoside phosphorylase (PNP)	+
HG1103-HT1103	Guanine Nucleotide-Binding prot Ral	+
X12447	aldolase A (ALDOA) (EC 41213)	−
X95826	ART4/X95826	+
D78514	ubiquitin-conjugating enzyme	+
M76424	carbonic anhydrase VII (CA VII)	+
D12775	erythrocyte-specific AMP deaminase; Also: U29926_2	+
U83192	post-synaptic density prot 95 (PSD95)	−
D87073	zinc finger protein znf142/KIAA0236	+
S50017	2,3-cyclic nucleotide 3-phosphodiesterase (CNP)	+
X07618	cytochrome P450 db1 variant a; Also: X07619, X16866	+
X67683	keratin 4 (KRT4)	+
M55543	guanylate binding prot isom II (GBP-2)	−
U08096	peripheral myelin prot-22 (PMP22) non-coding 1B/U08096	−
HG3141-HT3317	Nadh-Ubiquinone Oxidoreductase, 39 Kda Subunit	+
L46720	autotaxin-t (atx-t); Also: L35594	−
X98248	Sortilin (SORT1)	+
M13241	N-myc	−
U65581	ribosomal prot L3-like	+
U58334	Bcl2 p53 binding prot Bbp/53BP2 (BBP/53BP2)	+
S50223	HKR-T1 = Kruppel-like zinc finger prot	+
D13435	phosphatidyl-inositol-glycan class F	+
L37378	Acc# L37378	−
U16307	glioma pathosis-related prot (GliPR)	+
L22650	early lymphoid activation prot (EPAG)	+
U49837	LIM prot MLP (CSRP3)	+
M32334	intercellular adhesion molecule 2 (ICAM-2)	+
U79294	clone 23748 phosphatidic acid phosphatase 2B (PPAP2B)	+
X16560	COX VIIc subunit VIIc of cytochrome c oxidase (EC 1931)	−
X54816	alpha-1-microglobulin-bikunin (AMBP)	+
M90656	gamma-glutamylcysteine synthetase (GCS)	+
HG2239-HT2324	Potassium Channel prot Z11585	+
M27394	B-lymphocyte cell-surface antigen B1 (CD20); Also: X12530	+
AC002073	WUGSC: DJ515N12/PAC clone DJ515N1/22q112-q22	+
M17733	thymosin beta-4	+
S78432	transmembrane 4 prot/S78432	−
S72904	APK1 antigen = MAb KI recognized	−
M80629	cdc2-like protein kinase 5 (CDC2L5)	+
U89335	Notch 4	+
L34657	platelet/endothelial cell adhesion molecule-1 (PECAM-1)	+
J00123	enkephalin	−
X70944	PTB-associated splicing factor; Also: X16850	+
X80909	alpha NAC nascent polypeptide-associated complex	−
L37042	casein kinase I alpha isom (CSNK1A1)	+
X05196	aldolase C	+
U40215	synapsin IIb	+
D87460	paralemmin/KIAA0270	+
M37435	macrophage-specific colony-stimulating factor (CSF-1)	+
M94046	zinc finger prot (MAZ)	−
X69433	mitochondrial isocitrate dehydrogenase (NADP+)	−
U80017	Survival motor neuron protein (SMN)	−
M33336	cAMP-dependent prot kinase type I-alpha subunit (PRKAR1A)	+
D38503	PMS8 (yeast PMS1 homolog	+
HG3123-HT3299	Homeotic prot Gbx2	+
Y08302	MAP kinase phosphatase 4	−
L10405	DNA binding prot surfactant prot B/L 10405	−
X80026	B-cam	+
X59932	C-SRC-kinase; Also: X60114	+
Y10812	fructose-bisphosphatase	+
U79295	clone 23961 sequence	+
X51804	PMI a putative receptor prot	−
U23430	Cholecystokinin type A receptor (CCKAR); Also: L19315	+
M28879	granzyme B/CTLA-1 (GZMB)	+
L15326	endoperoxide synthase type II; Also: D28235, U04636_rna1	+
L32977	ubiquinol cytochrome c reductase Rieske iron-sulphur protein	−
D50925	serine-threonine protein kinase/KIAA0135	+
U28049	TBX2 (TXB2)	−
M29277	isolate JuSo MUC18 glycoprot (3′ variant)	−
U88726	symplekin/U88726	+
U63541	expressed in HC/HCC livers and MolT-4 proliferating cells	+
U80811	Lysophosphatidic acid receptor homolog (EDG2)	−
U02683	Nuclear respiratory factor 1 (NRF1); Also: L22454, U18383	+
S75463	P43 = mitochondrial elongation factor homolog	−
D31767	DAZ associated protein 2/KIAA0058	+
HG2320-HT2416	Integrin Beta 3 Subunit	+
HG3514-HT3708	Tropomyosin Tm30nm Cytoskeletal	+
U40714	tyrosyl-tRNA synthetase (YARS)	+
D16181	PMP2	+
D79999	VPARP vault protein/KIAA0177	+
M35999	platelet glycoprot IIIa/Integrin beta 3 (ITGB3)	+
M21186	neutrophil cytochrome b light chain p22	+
M28713	NADH-cytochrome b5 reductase (b5R)	−
U59309	fumarase precursor (FH) nuclear encoding mitochondrial prot	−
U64863	HPD-1 (hPD-1)	−
HG4194-HT4464	Sodium/Hydrogen Exchanger 5	+
Z83336	hH2B/d	+
D50402	Natural resistance associated macrophate prot1 (NRAMP1)	+
J04088	DNA topoisomerase II (top2)	+
X65644	MBP-2 MHC binding prot 2	+
M31627	X box binding prot-1 (XBP-1)	+
L06633	TRANSCRIPTION FACTORS	+
D50550	Lethal giant larvae homolog 1 (LLGL1)	+
U25265	MEK5	+
J05614	proliferating cell nuclear antigen (PCNA)	+
X13451	HG2563-HT2659 Same Uni Cluster as U05259	−
U10868	aldehyde dehydrogenase ALDH7	+
L75847	Zinc finger prot 45 (ZNF45)	+
HG644-HT644	Histone H1.1 (HIST1H1A)	−
Z84721	cosmid from 16p13.3 Contains alpha and zeta globin	+
HG2149-HT2219	Mucin/M57417	+
L21936	succinate dehydrogenase flavoprot subunit (SDH)	−
U01212	olfactory marker prot (OMP)	+
U14193	TFIIA gamma subunit	−
X68486	A2a adenosine receptor	+
Z48633	retrotransposon	−
D87685	TFIIS-like PHD finger protein 3/KIAA0244	+
U18062	TFIID subunit TAFII55 (TAFII55)	−
X95808	prot encoded by DXS6673E, for mental retardation/AB002383	+
U38276	semaphorin III family homolog (SEMA3F)	−
M64497	apolipoprot Al regulatory prot (ARP-1)	−
U79526	orphan G-prot coupled receptor Dez isoform a	−
HG4167-HT4437	Nuclear Factor 1 A Type	+
M31520	Ribosomal S24	−
U00238	glutamine PRPP amidotransferase (GPAT)	−
K02777	T-cell receptor active alpha-chain from Jurkat cell line/M12959	+
L22342	nuclear phosphoprot	+
U58087	Hs-cul-1	+
X81892	G protein-couped receptor 64 (GPR64)	+
U70323	ataxin-2 (SCA2)	−
S77812	flt = vascular endothelial growth factor receptor/VEGF receptor	+
D50918	septin 2, 6 (SEPT6)/KIAA0128	+
X13839	vascular smooth muscle alpha-actin	−
S76617	protein tyrosine kinase (BLK)	+
HG36-HT4101	PM-Sc1 autoantigen/M58460	−
U12535	epidermal growth factor receptor kinase substrate (EPS8)	−
X80590	PHKG1	+
M58028	ubiquitin-activating enzyme E1 (UBE1)	−
D13634	Hypothetical protein/KIAA0009	+
M68891	GATA-binding prot (GATA2)	+
AB000449	VRK1	+
S73885	AP-4 = basic helix-loop-helix DNA-binding prot; Also: X57435	−
U07807	metallothionein IV (MTIV)	+
U95626	ccr5	+
L13977	prolylcarboxypeptidase (PRCP)	−
J05068	transcobalamin I	+
U71087	MAP kinase kinase MEK5b	+
M57763	ADP-ribosylation factor (hARF6)	+
M98528	neuron-specific prot last clone D4S234	+
U67963	lysophospholipase homolog (HU-K5)	−
M20218	coagulation factor Xl	+
U93049	SLP-76 associated prot	+
HG1102-HT1102	Ras-Related C3 Botulinum Toxin Substrate (RAC1)	−
HG1428-HT1428	Globin, Beta; Also: U01317_6	+
M94172	N-type calcium channel alpha-1 subunit (CACNA1B)	+
U81556	hypothetical prot A4	+
M80244	E16	+
L40387	thyroid receptor interactor TRIP14 (OASL)	+
U67932	cAMP phosphodiesterase (Pde7A2)/U67932; Also: L12052	+
U68494	Hbc647 sequence	+
U01317	Beta-globin thalassemia	+
HG2705-HT2801	Serine/Threonine Kinase Z25427-Also: X97630	+
M63573	secreted cyclophilin-like prot (SCYLP)	−
D86959	hSLK serine threonine kinase/KIAA0204	+
HG3570-HT3773	prot Phosphatase Inhibitor Homolog	−
U80457	TRANSCRIPTION FACTORS SIM2 short form	−
U97018	echinoderm microtubule-associated prot homolog HuEMAP	−
U90547	Ro/SSA ribonucleoprot homolog (RoRet)	−
HG821-HT821	Ribosomal prot S13	+
Z29505	nucleic acid binding prot sub23	+
X84213	BAK BCI-2 homolog; Also: U16811, U23765	+
D28235	PTGS2 prostaglandin endoperoxide synthase-2/U04636_rna1	+
L33842	type II inosine monophosphate dehydrogenase (IMPDH2)	−
U30521	P311 HUM -31	−
X64330	ATP-citrate lyase	−
X15341	COX Vla-L cytochrome c oxidase liver-specific subunit Via	−
U82010	heme A: farnesyltransferase (COX10)	−
X73478	hPTPA	−
D32001	serum amyloid A1 gamma	+
X03342	ribosomal prot L32	−
HG3117-HT3293	Mps1	+
U65093	Msg1-related 1 (mrg1)	+
U28831	prot immuno-reactive with anti-PTH polyclonal antibodies	+
U41766	metalloprotease/disintegrin/cysteine-rich prot precursor MDC9	−
Z49269	chemokine HCC-1 (CCL14)	+
S65738	Actin depolymerizing factor	−
X56692	C-reactive prot	+
U52522	arfaptin 2 putative target prot of ADP-ribosylation factor	−
X64364	M6 antigen	−
Z22548	thiol-specific antioxidant peroxiredoxin 2 (PRDX2)	−
U04806	U03858 and others	+
L34059	cadherin-4	−
M21188	insulin-degrading enzyme (IDE)	−
L34060	cadherin-8	+
HG4704-HT5146	Glial Growth Factor 2	+
M73077	glucocorticoid receptor repression factor 1 (GRF-1)	−
M32011	neutrophil oxidase factor (p67-phox)	+
HG3914-HT4184	Cell Division Cycle prot 2-Related prot Kinase Pisslre/X78342	+
HG1783-HT1803	Islet Amyloid Polypeptide; Also: X81832	+
X53416	Actin-binding prot (filamin) (ABP-280)	−
Z84497	chrom 6 cosmid contains RING3, CpG Island; Also: Z96104_1	+
X63131	My1 (PML); Also: M73778	−
HG2815-HT2931	Unknown function prot	−
U90913	clone 23665 sequence	−
U70735	34 kDa mov34 isologue/U70735	−
Y00062	T200 leukocyte common antigen (CD45 LC-A)	+
L04270	(clone CD18) tumor necrosis factor receptor 2 related prot	−
J02854	20-kDa myosin light chain (MLC-2)	−
U37408	C-terminal binding protein 1 (CTBP1)	−
U48736	serine/threonine-prot kinase PRP4h (PRP4h)	+
X12530	B lymphocyte antigen CD20 (B1f, Bp35); Also: X07203	+
M83738	prot-tyrosine phosphatase (PTPase MEG2)	+
X15331	phosphoribosylpyrophosphate synthetase subunit one/D00860	+
D13370	APEX nuclease (APEX1)	+
U52700	tenascin-X (XB) RACE clone N1/U52700	+
M95809	Basic TRANSCRIPTION FACTORS 62 kD subunit (BTF2)	+
HG3638-HT3849	Amyloid Beta (A4) Precursor prot; Also: Y00264	−
L14595	alanine/serine/cysteine/threonine transporter (ASCT1)	+
U31342	nucleobindin	+
U45880	X-linked inhibitor of apotosis prot XIAP	+
S71129	acetylcholinesterase (ACHE)	+
D00760	proteasome subunit HC3	+
HG3254-HT3431	Phosphatidylinositol 3-Kinase P110 Beta	+
M64099	gamma-glutamyl transpeptidase-related prot (GGT-Rel)	−
M98539	prostaglandin D2 synthase	−
X59812	CYP 27 vitamin D3 25-hydroxylase	+
D79986	bcl-2-associated transcription factor/KIAA0164	+
U57342	myelodysplasia/myeloid leukemia factor 2 (MLF2)	−
X15187	tra1 homolog of murine tumor rejection antigen gp96	−
U79275	Clone 23947	+
L10338	sodium channel beta-1 subunit (SCN1B)/U12194/L16242	+
HG2247-HT2332	Major Intrinsic prot	+
X16609	ankyrin (variant 2.1); Also: HG2737-HT2837	−
D50810	placental leucine aminopeptidase	+
U43292	MDS1B (MDS1)	−
D14664	Lectin C domain-containing protein homolog/KIAA0022	+
X98253	ZNF183/X98253	+
S75256	HNL = neutrophil lipocalin; Also: X99133	+
Z24727	tropomyosin isoform	−
J02883	Colipase (CLPS)	+
M83221	I-Rel	+
D83260	HXC-26; Also: D83389	−
J05682	subunit C of V-ATPase (vat C)	+
M15841	U2 small nuclear RNA-associated B' antigen	−
D21852	hypothetical protein/KIAA0029	+
U11861	G10 homolog (edg-2)	−
X72755	Humig	−
L16896	zinc finger prot	−
X81003	HCG V	+
U37012	cleavage and polyadenylation specificity factor	+
M22638	LYL-1 prot	+
X52221	ERCC2	+
AF006084	Arp2/3 prot complex subunit p41-Arc (ARC41)	+
M83088	phosphoglucomutase 1 (PGM1)	−
D79989	centaurin gamma-1/KIAA0167	+
M75715	TB3-1; Also: X81625	−
J05582	Mucin 1 (MUC1); Also: J05581	−
L49219	retinoblastoma susceptibility prot (RB1) deletion mutant	+
M93284	pancreatic lipase related prot 2 (PLRP2)	+
M67468	Fragile X mental retardation 1 FMR-1; Also: X69962, L19493	+
U43965	ankyrin G119 (ANK3)	+
U60060	FEZ1	−
U86136	telomerase-associated prot TP-1	−
M19267	tropomyosin; Also: X12369	−
X78686	Chemokine (C-X-C motif) ligand 5 (CXCL5)	+
D28915	hepatitis C-associated protein p44 (IFI44)	+
U78027	L44L (L44-like ribosomal prot)	+
U71300	snRNA activating prot complex 50 kD subunit (SNAP50)	+
V00565	preproinsulin; Also: M10039	+
HG2566-HT4867	Microtubule-Associated prot Tau	+
D86331	MT2-MMP matrix metalloprot; Also: Z48482	−
M81933	Cell division cycle 25A (CDC25A)	+
L33801	prot kinase	−
S67070	heat shock prot HSP72 homolog	−
M63262	5-lipoxygenase activating prot (FLAP)	+
X02761	fibronectin (FN precursor); Also: HG3044-HT2527	−
M65214	(HeLa) helix-loop-helix prot HE47 (E2A); Also: M31523	+
HG2815-HT2931	Myosin, Light Chain/U02629; Also: HG2815-HT1357, M22919	−
U18009	chromosome 17q21 clone LF113	−
D49818	fructose 6-phosphate 2-kinase/fructose 2 6-bisphosphatase	−
HG2755-HT2862	T-Plastin	−
X04143	bone gla prot (BGP)	−
U40282	integrin-linked kinase (ILK)	−
Z50022	surface glycoprot	−
U22055	100 kDa coactivator	−
M94880	MHC class I (HLA-A*8001); Also Similar To: M80469_rna1	+
D38122	Fas ligand	+
M93405	methylmalonate semialdehyde dehydrogenase (ALDH6A1)	+
X79780	YPT3	−
U17969	initiation factor eIF-5A	−
X51466	elongation factor 2	−
Z74616	prepro-alpha2(I) collagen; Also: J03464	−
D78367	K12 keratin	+
L28821	alpha mannosidase II isozyme	−
M29536	translational initiation factor 2 beta subunit (eIF-2-beta)	−
Y07829	RING prot	+
X97324	adipophilin (ADFP)	+
X56494	M M1-type and M2-type pyruvate kinase	−
L15533	Pancreatitis associated prot	−
L15388	G prot-coupled receptor kinase (GRK5)	−
U78521	immunophilin homolog ARA9	+
L07541	replication factor C 38-kDa subunit	+
M25667	neuronal growth prot 43 (GAP-43)	+
X82279	Fas, Apo-1/X82279; Also: D31968	+
X83490	Fas/Apo-1/X83490; Also: X83493, X63717	+
M81780	Sphingomyelin phosphodiesterase 1 (SMPD1)	+
U59748	Desert hedgehog (hDHH)/U59748/	+
D42073	reticulocalbin	−
L37792	syntaxin 1A	+
M96233	glutathione transferase class mu number 4 (GSTM4)/M99421	−
U18919	chromosome 17q12-21 clone pOV-2	−
U09087	thymopoietin (TMPO); Also: U09088	+
X63097	Rhesus polypeptide RhXIII	+
U22431	hypoxia-inducible factor 1 alpha (HIF-1 alpha)/X72726, U29165	−
X75593	rab 13	−
D63486	hypothetical protein/KIAA0152	−
M23114	calcium-ATPase (HK1)	−
M17885	Acidic ribosomal phosphoprot P0	−
U28014	cysteine protease (ICErel-II)	+
X84195	acylphosphatase muscle type (MT) isoenzyme	+
Z80787	Histone H4	+
U58048	metallopeptidase PRSM1	−
M24899	triiodothyronine (ear7)	−
M63928	T cell activation antigen (CD27)	+
M55210	laminin B2 chain (LAMB2)	−
HG4460-HT4729	lg Heavy Chain Vdjc Regions	+
X85116	epb72; Also: U33931 Same Unigene Cluster as M81635.	−
U20908	melanoma ubiquitous mutated prot (MUM-1)/U20908	−
D50532	macrophage lectin 2 (HML2)	+
Z68274	DNA sequence from Huntingtons Disease Region/Z68274	+
D50915	hypothetical protein/KIAA0125	+
D38550	E2f-3 transcription factor/KIAA0075	+
M80333	m5 muscarinic acetylcholine receptor	+
Z24725	mitogen inducible mig-2	−
U08815	splicesomal prot (SAP 61)	−
U30313	diadenosine tetraphosphatase (NUDT2)	−
D42044	hypothetical protein/KIAA0090	+
U32849	Hou	+
Z31357	cysteine dioxygenase type 1	+
M95787	22 kDa smooth muscle prot (SM22)	−
X76732	NEFA prot (DNA-binding leucine zipper Ca-binding EF-hand)	−
M74002	arginine-rich nuclear prot	−
L35249	vacuolar H+-ATPase Mr 56,000 subunit (HO57); Also: M60346	+
U17760	laminin S B3 chain (LAMB3)	+
D42053	Site-1 protease transcription factor/KIAA0091	+
D49817	fructose 6-phosphate 2-kinase/fructose 2 6-bisphosphatase	−
U30255	phosphogluconate dehydrogenase (hPGDH)	+
M86917	oxysterol-binding prot (OSBP)	+
M16714	MHC class I divergent lymphocyte antigen; clone RS5	+
X59842	PBX2; Also: U89336_2, D28769_1, X80700_rna1	−
HG37-HT37	HG37-HT37	+
L05628	multidrug resistance-associated prot (MRP); Also: X78338	+
U38980	PMS2 related (hPMSR6)	+
U27193	prot-tyrosine phosphatase	−
HG3255-HT3432	Gaba A Receptor Beta 2 Subunit	+
D88422	DNA cystatin A	+
U59289	H-cadherin	−
M12125	fibroblast muscle-type tropomyosin,	−
J05016	prot disulfide isomerase related prot (ERp72); Also: J05016	+
D63478	Hypothetical protein/KIAA0144	−
D29954	hypothetical protein/KIAA0056	+
X06318	protein kinase C (PKC) type beta I (PRKCB)	+
L35240	enigma	−
U49070	peptidyl-prolyl isomerase and essential mitotic regulator PIN1	−
L10413	farnesyltransferase alpha-subunit	−
X82634	hair keratin acidic 3B (KRTHA3B)	+
M91463	glucose transporter (GLUT4)	+
L19779	histone H2A2	+
S69790	Brush-1 = tumor suppressor	+
D55640	monocyte pseudoautosomal boundary-like sequence	−
D49357	S-adenosylmethionine synthetase	+
U73304	CB1 cannabinoid receptor (CNR1) .	+
U52154	G prot-coupled inwardly rectifying potassium channel Kir34	+
Z23090	28 kDa heat shock prot	−
S76756	4R-MAP2 = microtubule-associated prot 2 4R isoform/S76756	+
X86018	MUF1 prot	+
X97444	transmembrane prot Tmp21-IIex. /X97444	+
U35234	prot tyrosine phosphatase sigma	+
U41515	deleted in split hand/split foot 1 (DSS1)	−
U58970	outer mitochondrial membrane translocase (TOMM34)	−
D49824	HLA-B null allele; Also: L42345 and others	+
L11672	Kruppel related zinc finger prot (HTF10)	+
M16336	T-cell surface antigen CD2 (T11); Also: M14362	+
U12404	Csa-19	−
M74091	Cyclin C	+
U73737	HMSH6	−
U62801	protease M	+
X97267	LPAP; Also: X81422	+
D87845	platelet-activating factor acetylhydrolase 2	+
L42243	IFNAR2 (interferon receptor)	+
M64595	Small G prot (Gx)	+
L25286	Alpha-1 type XV collagen; Also: L25285	−
HG3513-HT3707	Myosin, Heavy Polypeptide, Light Meromyosin	+
Y09836	unknown prot	−
X97335	kinase A anchor prot	−
HG1155-HT4822	Colony-Stimulating Factor 1 Macrophage (CSF1)	+
HG2007-HT2056	Proto-Oncogene Sno; Also: HG2007-HT5112	+
M61764	gamma-tubulin	−
AF001548	myosin heavy chain from chromosome 16	−
L07044	Ca-Calmodulin-dependent prot kinase CAMK	−
D31889	26S proteasome subunit S5 basic/KIAA0072	−
Z49989	smoothelin	−
M34344	platelet glycoprot IIb (GPIIb)	+
L04490	NADH-ubiquinone oxidoreductase subunit (NDUFA9)	−
X52896	dermal fibroblast elastin; Also: HG2994-HT4851	+
J05272	IMP dehydrogenase type 1	+
L26339	autoantigen	−
L42374	PP2A B56-beta; Also: Z69028	+
U20350	G prot-coupled receptor V28	+
X84194	acylphosphatase erythrocyte (CT) isoenzyme	+
X61587	rhoG GTPase	+
U02566	receptor tyrosine kinase TIF; Also: U18934	−
X52979	SmB prot from small nuclear ribonucleoprots; Also: X17567	−
U19523	GTP cyclohydrolase 1	+
X06825	skeletal beta-tropomyosin	−
J04611	lupus p70 (Ku) autoantigen prot	−
U43527	malignant melanoma metastasis-suppressor (KiSS-1)	−
X98743	RNA helicase (Myc-regulated dead box prot)	+
L10844	cellular growth-regulating prot	−
U43203	Thyroid transcription factor 1 (TTF-1); Also: U33749	+
U50327	prot kinase C substrate 80K-H (PRKCSH); Also: J03075	+
L41690	TNF receptor-1 associated prot (TRADD)	+
M99701	pp21	−
V00594	metallothionein 2A (MT2A); Also: J00271	−
U40992	heat shock prot hsp40 homolog	+
M33374	cell adhesion prot (SQM1)	−
HG831-HT831	Potassium Channel	+
HG658-HT658	Major Histocompatibility Complex, Class I, C X58536)	+
U68019	mad prot homolog (hMAD-3)	−
D16581	8-oxo-dGTPase	+
L14813	carboxyl ester lipase like prot (CELL)	+
X13973	ribonuclease/angiogenin inhibitor (RAI)	−
L10377	(clone CTG-B37) sequence; Also: D38529, U23851, D31840	−
Z68129	NAD(H)-specific isocitrate dehydrogenase gamma-subunit	−
L19783	GPI-H	−
HG4018-HT4288	Opioid-Binding Cell Adhesion Molecule	+
L10910	splicing factor (CC13)	−
U30246	bumetanide-sensitive Na-K-CI cotransporter (NKCC1)	−
HG4683-HT5108	TNF Receptor 2 Associated prot Trap3; Also: U12597	−
M31013	nonmuscle myosin heavy chain (NMHC)	−
U94832	KH type splicing regulatory prot KSRP	−
S69272	38 kda intracellular serine protase inhibitor; Also: Z22658	−
U76010	putative zinc transporter ZnT-3 (ZnT-3)	+
L39064	IL-9 receptor	−
M73547	polyposis locus (DP1 )	−
HG2668-HT2764	Bradykinin Receptor	+
Z50115	Thimet oligopeptidase (metalloproteinase); Also: U29366	−
M21259	Alu repeats in the region to the Snrp E	−
X95073	translin associated prot X	+
V01516	cytoskeletal keratin (type II) from foreskin	+
X70940	elongation factor 1 alpha-2; Also: L10340	−
D16350	SA	+
AF007551	Bet1p homolog (hbet1)	+
D50692	c-myc binding prot	+
U34044	selenium donor prot (selD)	−
U48959	myosin light chain kinase (MLCK)	−
U54644	tub homolog; Also: U82467	−
U59057	beta-A4 crystallin (CRYBA4)	−
U66559	anaplastic lymphoma kinase receptor	−
L11701	phospholipase D; Also: L11702	+
L39874	deoxycytidylate deaminase	+
U33052	lipid-activated, prot kinase PRK2; Also: S75548	+
U18671	Stat2	+
M59371	prot tyrosine kinase	+
Y10615	CYRN2/Y10615	+
HG4116-HT4386	Olfactory Receptor Or17-219; Also: HG4108-HT4378	−
U15460	bZip prot B-ATF	+
X62822	beta-galactoside alpha-26-sialyltransferase	+
U22233	methylthioadenosine phosphorylase (MTAP)	+
X59710	CAAT-box DNA binding prot subunit B (NF-YB)	+
D87077	hypothetical protein/KIAA0240	+
U31875	Hep27 prot.	−
D29956	ubiquitin specific protease 8/KIAA0055	+
U30998	(nmd)/U30998	−
U23852	X13529, X05027 and others	+
Y07847	RRP22 prot	+
M93107	heart (R)-3-hydroxybutyrate dehydrogenase end	+
Z22551	kinectin	−
HG1800-HT1823	Ribosomal prot S20	+
D13635	ubiquitin-protein isopeptide ligase E3/KIAA0010	+
M19961	cytochrome c oxidase subunit Vb (coxVb)	−
X82850	thyroid transcript factor 1; Also: U43203, U33749	−
S82447	GCN5-like 1 = GCN5 homolog/Also: D64007	−
M16364	creatine kinase-B; Also: X15334_rna1	−
M10612	apolipoprot C-II	+
X13293	v-myb myeloblastosis viral homolog-like 2 (MYBL2)	−
U47101	NifU-like prot (hNifU)	−
U65579	mitoch NADH dehydrogenase-ubiquinone Fe-S prot 8 23 kDa	−
D10995	serotonin 1B receptor	+
U51586	siah binding prot 1 (SiahBP1)	−
D50477	membrane-type matrix metalloproteinase 3; Also: D83646	+
S45630	alpha B-crystallin = Glioma Rosenthal fiber component	−
J02923	65-kilodalton phosphoprot (p65)	+
S85655	prohibitin (PHB)	−
X14046	leukocyte antigen CD37	+
U57627	fetal brain oculocerebrorenal syndrome (OCRL1)	−
M26004	CR2/CD21/C3d/Epstein-Barr virus receptor; Also: J03565	+
HG1980-HT2023	Tubulin, Beta 2	−
U07231	G-rich sequence factor-1 (GRSF-1)	−
M86528	neurotrophin-4 (NT-4)	+
D28476	thyroid hormone receptor interactor 12/KIAA0045	+
U73167	H_LUCA146	−
U37146	silencing mediator of retinoid and thyroid hormone (SMRT)	−
D64053	prot-tyrosine phosphatase	−
D14889	small GTP-binding protein S10 (RAB33A)	+
X52638	6-phosphofructo-2-kinase/fructose-26-bisphosphatase	+
U96629	Hereditary multiple exostosis	−
M85247	dopamine D1A receptor/M85247	−
Y08263	AAD14 prot	+
X57766	stromelysin-3	−
D13644	tre oncogene homolog/KIAA0019	+
U77665	RNaseP prot p30 (RPP30)	−
X74104	TRAP beta subunit	−
D78132	Ras homolog enriched in brain (RHEB); Also: Z29677	−
U79271	clones 23920 and 23921 sequence	−
X52851	peptidylprolyl isomerase from cyclophilin (EC 5.2.1.8)	−
U19977	preprocarboxypeptidase A2 (proCPA2)	+
X04470	antileukoprotease (ALP) from cervix uterus; Also: X04503	+
D30742	calmodulin-dependent prot kinase IV	+
D26070	type 1 inositol 145-trisphosphate receptor	−
U03399	T-complex prot 10A (TCP10A)	+
X03068	HLA-D class II antigen DQw1.1 beta chain	+
X77548	RFG	+
U07418	DNA mismatch repair (hmlh1)	−
U73799	dynactin/U73799	+
X54667	cystatin S; Also: S51222, M19169	−
L40397	(clone S31i125)	−
M23533	alpha 2 adrenergic receptor	+
U11732	ets-like (tel)	+
D17400	6-pyruvoyl-tetrahydropterin synthase	−
D11086	interleukin 2 receptor gamma	+
M24248	MLC-1V-Sb	+
M20867	glutamate dehydrogenase (GDH); Also: HG4200-HT4470	+
L38820	HMC class I antigen-like glycoprot (CD1D)	+
J04132	T cell receptor zeta-chain	+
M31932	lgG low affinity Fc fragment receptor (FcRlla)	+
X14008	lysozyme (EC 3.2.1.17)	+
U63295	Seven in absentia homolog	−
U06631	(H326)	−
X80822	ORF	+
L01406	growth hormone-releasing hormone receptor	+
M68895	alcohol dehydrogenase 6	−
X60036	mitochondrial phosphate carrier prot	−
M25079	Sickle cell beta-globin; Also: U01317_6, HG1428-HT1428	+
X69978	XP-G factor	−
L08835	DM kinase (myotonic dystrophy kinase)/HG2486-HT2582	−
M34668	prot tyrosine phosphatase (PTPase-alpha)	−
U61145	enhancer of zeste homolog 2 (EZH2)	−
U62966	Na+/nucleoside cotransporter (hCNT1a)	−
L19401	myosin I homolog (MYH12)	+
U85767	myeloid progenitor inhibitory factor-1 (MPIF1)	+
U94586	NADH: ubiquinone oxidoreductase MLRQ subunit	−
L13972	beta-galactoside alpha-23-sialyltransferase (SIAT4A)	−
X57152	casein kinase II subunit beta (EC 2.7.1.37); Also: M30448	−
U50950	infant brain unknown product	−
X15882	collagen VI alpha-2 C-terminal globular domain	−
U09850	zinc finger prot (ZNF143)	+
X76013	QRSHs glutaminyl-tRNA synthetase	−
X05855	histone H3.3; Also: M11353	+
X16663	HS1 heamatopoietic lineage cell specific prot	+
M22760	mitochondrial cytochrome c oxidase Va subunit	−
HG3412-HT3593	Blue Cone Photoreceptor Pigment; Also: M13299	+
U47292	spasmolytic polypeptide (SP)	+
X13546	put. HMG-17 non-histone prot	−
M18000	ribosomal prot S17	−
Z68193	Opsin 1 (OPN1LW)	+
L49173	OCP2/L49173	+
X85750	monocyte to macrophage differentiation-associated prot	+
X84373	nuclear factor RIP140	−
D87743	Sodium/hydrogen exchanger 6/KIAA0267	+
Z12173	GNS glucosamine-6-sulphatase	+
U60115	skeletal muscle LIM-prot SLIM1	−
HG4263-HT4533	Nkr-P1a prot	+
U30245	myelomonocytic specific prot (MNDA)/U30245	+
X72841	IEF 7442	−
M64571	microtubule-associated prot 4	−
M23294	beta-hexosaminidase beta-subunit (HEXB)	−
J03133	TRANSCRIPTION FACTORS SP1	+
L40636	(clone FBK III 16) prot tyrosine kinase (NET PTK)	−
X54870	NKG2-D	+
M26167	platelet factor 4 varation 1 (PF4var1)	+
U59058	beta-A3/A1 crystallin (CYRBA3/A1); Also: M14306	+
U89336	Notch 4	+
Z11559	iron regulatory factor	−
HG4322-HT4592	Tubulin, Beta	−
X06256	fibronectin receptor alpha subunit	−
U13395	oxidoreductase (HHCMA56)	+
D79990	Ras association domain family 2/KIAA0168	+
U90916	clone 23815 sequence, IFN-inducible	+
AB002318	talin homolog/KIAA0320	+
X55448	G6PD glucose-6-phosphate dehydrogenase; Also: M65234	+
D89016	Neuroblastoma	+
U13737	cysteine protease CPP32 isom alpha	−
U11690	faciogenital dysplasia (FGD1)	−
X02176	complement component C9; Also: K02766	−
HG2075-HT2137	Camp-Responsive Element Modulator; D14825, S68134	+
U39400	NOF1	−
U68723	checkpoint suppressor 1	−
L11373	protocadherin 43	−
D25216	hypothetical protein/KIAA0014	−
U13695	homolog of yeast mutL (hPMS1)	+
U67611	Mouse transaldolase/U67611	+
X84746	Histo-blood group AB0 1	−
AF012270	peropsin (Rrh)	−
J03925	Mac-1 encoding complement receptor type 3 CD11b	+
Z74792	CCAAT transcription binding factor subunit gamma/S74703	−
U79300	clone 23629 sequence	+
M11313	alpha-2-macroglobulin; Also: M36501	−
M30838	pulmonary surfactant apoprot (PSAP)	+
HG1595-HT4788	Heterogeneous Nuclear Ribonucleoprot I/X66975	+
M27396	asparagine synthetase; Also: M15798	−
L48513	paraoxonase 2 (PON2)	−
U50939	amyloid precursor prot-binding prot 1	−
L41607	beta-16-N-acetylglucosaminyltransferase (IGnT)	+
D00654	Enteric smooth muscle gamma-actin	−
Y12711	putative progesterone binding prot	+
D86963	dishevelled 3/KIAA0208	+
L37043	Casein kinase I epsilon	−
U60415	bHLH-PAS prot Jap3	+
L76937	unnamed prot product from Werner syndrome	+
X98258	M-phase phosphoprot mpp9	+
M14636	liver glycogen phosphorylase	+
V00571	Prepro form of corticotropin releasing factor	−
D55696	cysteine protease	−
U79272	clone 23720 sequence	+
M27691	transactivator prot (CREB)	+
U52111	Plexin related prot	−
U83239	CC chemokine STCP-1; Also: U83171	+
X61072	T cell receptor, clone IGRA17	+
S71824	N-CAM	−
M27093	alpha-keto acid dehydrogenase transacylase subunit E2b	+
U19878	transmembrane prot	+
HG2649-HT2745	Serine/Threonine prot Kinase Cdk3; Also: X66357	−
D89289	N-Acetyl-beta-D-glucosaminide	+
L33243	polycystic kidney disease 1 prot (PKD1)	−

[0044]

TABLE 13
Highest discriminatory genes for MS vs. MS on Avonex
(i.e., genes modified by Avonex).
		Up (+) or
Probe sets	Gene Descriptions	down (−)
U60115	Four and a half LIM skeletal muscle SLIM1	+
	(FHL1)
X80878	R kappa B (NFRKB)	+
AF001548	815A9.1 myosin heavy chain (MYH11)	−
K03008	Gamma G2 psi from gamma crystalline	−
	(CRYGEP1)
Z19585	thrombospondin-4 (THBS4)	+
Z97054	PAC contains KIAA0178 similar to SMC1 and	+
	URE-B1

[0045]

TABLE 14
Intermediate discriminatory genes for MS vs. MS on
Avonex (i.e., genes modified by Avonex)
M94345	macrophage capping protein (CAPG)	−
M21665	beta-myosin heavy chain (MYH7); Also: X52889	+
M30448	X56597, M59849 and others	+
X16416	c-abl encoding p150 prot	+
Z75330	nuclear protein stromal antigen SA-1 (STAG1)	+
X79865	Mrp17/Mitochondrial ribosomal L12 (MRPL12)	−
X60483	H4/D histone	+
M96759	rod outer segment membrane prot 1 (ROM1)	−
M36284	glycophorin C (GYPC); Also: X12496	+
U88666	SFRS protein kinase 2 (SRPK2)	+
D86973	yeast translational activator Gcn1 homolog (GCN1L1)	+
U82130	tumor susceptibility protein (TSG101)	+
S80050	a-6-D-mannoside b-16-N-acetylglucosaminyltransferase V	+

[0046]

TABLE 15
Least discriminatory genes for MS vs. MS on
Avonex (i.e., genes modified by Avonex)
U90909	clone 23722 sequence	+
M22638	Lymphoblastic leukemia-derived sequence 1 (LYL1)	−
U07807	metallothionein IV (MTIV)	+
HG2825-	Ret Transforming	+
HT2949
X71428	Fus	+
S76617	protein tyrosine kinase (BLK)	+
HG1428-	Globin, Beta (HBB); Also: U01317_6	+
HT1428
S82597	UDP-GaINAc: N-acetylgalactosaminyltransferase	+
	(GALNT1)
U26710	cbl-b (CBLB)	−
X62078	GM2 activator protein (GM2A)	−
X76057	PMI1 phosphomannose isomerase	+
HG4677-	Oncogene Ret/Ptc2, Fusion Activated/M57464	−
HT5102
L10102	sex determining region Y (SRY)	−
M93143	plasminogen-like protein (PLGL)	+
U79261	clone 23959 (MAPK8IP2); Also: U62317	+
X59373	HOX4D homeobox protein	+
X83218	ATP synthase	+
M80563	Calcium-binding CAPL protein	−
M34458	lamin B1 (LMNB1); Also: M34458, L37747	−
L32866	effector cell protease receptor-1 (EPR-1)	+
U10117	endothelial-monocyte activating polypeptide II	−
U25138	MaxiK potassium channel beta subunit (KCNMB1)	−
U78095	Placental bikunin (AMBP)	+
D38550	E2F3 transcription factor/KIAA0075	+
X64878	oxytocin receptor (OXTR)	−
U70323	Ataxin-2 (SCA2)	−
D21878	Bone marrow stromal cell antigen 1 (BST1)	−
X90530	ragB protein	+
M31627	X box binding prot-1 (XBP-1)	+
Y10207	CD171 protein	+
U66559	anaplastic lymphoma kinase receptor (ALK)	−
L12723	heat shock prot 70 (hsp70) protein 4 (HSPA4)	−
D87685	TFIIS-like PHD finger protein 3/	+
	KIAA0244
J04982	adenine nucleotide translocator ANT1 (SLC25A4)	+
X65867	adenylosuccinate lyase (ADSL)	+
U83598	death domain receptor 3 soluble form DDR3	+
	(TNFRSF25)
M93426	prot tyrosine phosphatase zeta-polypeptide (PTPRZ1)	+
U01147	guanine nucleotide regulatory protein (ABR)	−
U78027	L44L (L44-like ribosomal protein)	−
D50911	hypothetical protein/KIAA0121	+
S77361	transcript ch132/S77361	−
X75252	phosphatidylethanolamine binding protein	+
L09235	vacuolar ATPase isom VA68 (ATP6V1A1)	−
X00274	HLA-DR alpha heavy chain a class II antigen	−
D11094	Proteasomal ATPase MSS1 (PSMC2)	−
M19483	ATP synthase beta subunit	−
U88964	HEM45	−
D87450	parallel sister chromatids drosophila protein-like/	+
	KIAA0261
U65406	KCNJ1 (from potassium channel ROM-K1-6)	−
X83492	Fas/APO1 (TNFRSF6)	+
U17077	BENE protein	+
U49352	liver 24-dienoyl-CoA reductase 1 (DECR1)	−
Z25535	nuclear pore complex protein hnup153	+
M21119	lysozyme (LYZ); Also: X14008_rna1, J03801, M19045	−
M87284	69 kDa 2′ oligoadenylate synthetase (P69 2-5A	−
	synthetase)
L15189	mortalin-2/L11066	+
U67784	orphan G protein-coupled receptor (RDC1)	−
D87076	Br140/KIAA0239	+
U10323	nuclear factor NF45	+
M34455	IFN-gamma-inducible indoleamine 23-dioxygenase	−
	(INDO)
M11147	ferritin L chain	−
L36033	pre-B cell stimulating factor homolog SDF1b (CXCL12)	+
Y07604	nucleoside-diphosphate kinase	+
M27543	guanine nucleotide-binding prot (Gi) alpha subunit	−
	(GNAI3)
S54005	thymosin beta-10; Also: M92383	−
AC002477	PAC clone DJ327A19 from Xq25-q26, AC002477/	+
	X98253
D80004	Hypothetical protein/KIAA0182	+
U34044	selenium donor prot selenophosphate synthetase (SPS)	+
M30607	zinc finger prot Y-linked (ZFY); Also: L10393	−
D38521	rat TEMO homolog/KIAA0077	+
X66401	LMP2 from TAP1, TAP2, LMP2, LMP7 and DOB	−
U00001	Cell division cycle 27 (CDC27)/S78234	−
D80005	hypothetical protein/KIAA0183	+
U56833	VHL binding protein-1 (VBP-1)	+
M27396	asparagine synthetase (ASNS); Also: M15798	+
X56253	MPR46 46 kd mannose 6-phosphate receptor (M6PR)	−
X77753	TROP-2 (TACSTD2)	+
J04040	Glucagon (GCG)	−
L14813	carboxyl ester lipase like prot (CELL)	−
AF003743	delayed rectifier potassium channel (KVLQT1-Iso5)	−
U52154	G prot-coupled inwardly rectifying potassium channel	+
	Kir34
U56998	putative serine/threonine protein kinase PRK	+
X99209	arginine methyltransferase	+
Z30643	chloride channel (CLCNKA)	−
D14662	anti-oxidant protein peroxiredoxin 6 (PRDX6)/	+
	KIAA0106
U32576	apolipoprot apoC-IV (APOC4)	−
D89377	Msh homeobox homolog 2 (MSX2)	−
L22005	ubiquitin conjugating enzyme	+
U03100	alpha2(E)-catenin	+
U05237	fetal Alz-50-reactive clone 1 (FAC1)	+
L05425	Autoantigen	−
J03909	gamma-interferon-inducible protein (IP30)	−
M22976	cytochrome b5	−
X97324	adipophilin (ADFP)	+
HG3369-	Potassium Channel Voltage-Gated lsk-Related	−
HT3546
D89859	zinc finger 5 protein (ZNF5)	+
X66363	PCTAIRE-1 serine/threonine prot kinase 1 (PCTK1)	−
D90084	pyruvate dehydrogenase alpha subunit 1 (PDHA1)	+
D13315	lactoyl glutathione lyase, glyoxalase 1 (GLO1)	+
J04101	NAD(P)H: menadione oxidoreductase; Also: M81600	−
U89012	dentin matrix acidic phosphoprotein 1 (DMP1)	−
D42041	alpha glucosidase 2 (G2AN)/KIAA0088	+
D31890	lysyl-tRNA synthetase (KARS)/KIAA0070	+
U53830	interferon regulatory factor 7A (IRF7)	−
U15085	HLA-DMB	−
L20941	ferritin heavy chain (FTH1)	−
X13293	v-myb myeloblastosis viral homolog-like 2 (MYBL2)	−
U07158	Syntaxin	−
M77144	3-b-hydroxysteroid dehydrogenase/5delta 4delta	+
	isomerase
X55079	GAA from lysosomal alpha-glucosidase 1	+
U79254	clone 23693 sequence	+
X98507	myosin-l beta	+
U44975	DNA-binding protein CPBP (CPBP)	−
U49278	putative DNA-binding protein	−
D85376	DNA thyrotropin-releasing hormone receptor (TRHR)	+
X85785	DARC, Duffy blood group (FY)	+
M19507	Myeloperoxidase (MPO)	−
M26311	M21064 and others; Calgranulin B (S100A9)	−
M26041	MHC class II DQ alpha 1 (HLADQA1); Also: M33906	−
M95929	Paired mesoderm homeobox protein 1 PHOX1 (PMX1)	−
X15414	aldose reductase (EC 1112)	+
L05188	small proline-rich protein 2 (SPRR2B)	+
L34219	retinaldehyde-binding protein (CRALBP)	−
X74262	RbAp48 encoding retinoblastoma binding protein	+
M88461	neuropeptide Y peptide YY receptor (NPY1R); L07615	−
M90696	cathepsin S (CTSS)	−
X54150	Fc receptor (FCAR)	−
M23254	Ca2-activated neutral protease large subunit (CANP)	−
M27891	cystatin C (CST3)	−
L20591	annexin III (ANX3) alternative	−
M57731	gro-beta; chemokine (C-X-C) motif ligand 2 (CXCL2)	−
U88902	endogenous retroviral integrase H and putative env prot	+
M59941	GM-CSF receptor beta chain (CSF2RB)	+
M80629	cdc2-like protein kinase 5 (CDC2L5)	+
X72790	endogenous retrovirus	+
D64015	T-cluster binding protein	+
D17516	PACAP receptor (ADCYAP1R1)	−
Z26491	catechol O-methyltransferase (COMT); Also: M65213	+
U91931	AP-3 complex beta3A subunit	−
X53002	integrin beta-5 subunit; Also: J05633	+
M12174	ras-related rho (clone 6)	−
X04500	prointerleukin 1 beta (IL1B)	−
D15057	Defender against cell death 1 (DAD1)	+
D50912	RNA-binding motif protein-10 (RBM10)/KIAA0122	+
M34338	spermidine synthase (SRM); Also: M64231_rna1	+

[0047]

TABLE 16
Preferred Genes List Number 1: Genes that discriminate blood
samples of MS (on no treatment) when compared to ALS and Healthy
donors, regardless of heterogeneity of the MS sample population.
		Up (+) or
Probe set	Gene description	down (−)
D30037	phosphatidylinositol transfer protein (PITPN)	+
D29675	Inducible nitric oxide synthase (iNOS)	+
Z25884	CIC-1 muscle chloride channel protein (CLCN1)	+
U78095	Placental bikunin (AMBP)	+
U14187	receptor tyrosine kinase ligand LERK-3/	+
	Ephrin-A3
L34357	GATA4	+
U18271	thymopoietin (TMPO)	+
HG2415-	transcription factor E2F2	+
HT2511

[0048] Tables 1-15 include comparisons of a homogeneous MS patient population (i.e., exclusively the relapsing-remitting type of MS, on Avonex or not, 5 samples each) with ALS (5 samples) or healthy donors (5 samples). To establish genes that were consistently discriminatory for MS regardless of patient sample heterogeneity, the inventors added a blood sample from an untreated patient who presented with tumefactive, tumor-like demyelinative lesions by MRI imaging (i.e., an extreme clinical variant of the disease refered to as “tumefactive” MS, which was confirmed by brain biopsy) and a patient with 6 years of symptoms of multiple sclerosis (confirmed by MRI imaging), now entering the secondary progressive phase of the disease and who had not previously received any specific treatment for her condition (total number of patients with MS=7). The inventors also added 2 blood samples from healthy donors (total=7) and 3 blood samples from ALS patients (total=8). They then performed a comparison of MS vs. ALS and healthy donors, and established the highest discriminatory genes that were shared with Tables 7-9 (which include only 5 samples in each group, including the homogeneous MS population). Among these shared discriminatory genes, they chose 8 top genes that are highly discriminatory in analyzing blood samples from untreated MS (regardless of heterogeneity of MS) when compared to healthy donors and/or other neurodegenerative (not primarily autoimmune) diseases (e.g., ALS) (Table 16). For purposes of uniformity, these 8 genes are shown in a comparison using 5 patients in each group (see FIG. 3).

TABLE 17
Preferred Genes List Number 2: Independent of Treatment or Controls
	Probe Set	Altered
Gene Description	Identification	In*
S-adenosylmethionine synthetase	X68836	1, 2, 3
(MAT2A)
Carcinoembryonic antigen	HG3175-HT3352	1, 2, 3
Ret transforming gene	HG2825-HT2949	1, 2, 3
G protein-linked receptor (clone	L42324	1, 2
GPCR W)
GTP-binding protein RALB	M35416	1, 2
Tyrosine kinase Syk	L28824	1, 2
T cell leukemia LERK-2 (Ephrin-B1)	U09303	1, 2
Tyrosine kinase (ELK1) oncogene	M25269	1, 2
Transcription factor SL1+	L39059	1, 3
Phospholipase c (PLCB3)+	Z16411	1, 3
Gastricsin (progastricsin)	U75272	2, 3
D13S824E locus+	U47635	2,3
*1: Avonex-treated heterogeneous MS and untreated heterogeneous MS vs. ALS and healthy
#donors; 2: untreated heterogeneous MS vs. ALS and healthy donors; 3: untreated heterogeneous
#MS vs. healthy donors
+downregulated genes

[0049] The second group of preferred genes, shown in Table 17, was generated by multiple group comparisons using the inventors' statistical method, with the goal being to identify a heterogeneous population of MS patients, regardless of treatment with interferon β1a, and regardless of control sample origin (healthy individuals or subjects with other neurodegenerative diseases used as controls). Heterogeneity is used in this context to refer to a population of patients with different phenotypic forms of MS (i.e., besides the classical relapsing-remitting clinical form with typical ovoid, pericallosal or periventricular lesions by MR imaging and little disability in its early stages). Such patients may have the secondary progressive form and may have accumulated more clinical disability, may not have any brain lesions but only optic nerve or spinal cord demyelinating lesions, may have brain atrophy by MR imaging, may have brain tumor-mimicking MS lesions (i.e., tumefactive MS), and may or may not be on treatment with interferon β1a. MS patients in the group ranged in age from 18 to 44 years (within the normal distribution for MS).

[0050] To generate the list in Table 17, the inventors repeated their analysis by further increasing the number of RNA samples in each group (by adding RNA samples from a new set of blood donors to the original homogeneous MS groups), which increased the stringency of selection of heterogeneous MS-associated genes. They compared 8 untreated MS samples (heterogeneous types of MS), 9 Avonex-treated heterogeneous MS samples, 7 healthy donor samples, and 8 ALS samples (total: 32 samples). The following comparisons among grouped classes were performed: (1) Avonex-treated heterogeneous MS and untreated heterogeneous MS vs. ALS and healthy donors (two groups total), which generated 25 discriminatory genes; (2) untreated heterogeneous MS vs. ALS and healthy donors (two groups total), which generated 27 discriminatory genes; (3) untreated heterogeneous MS vs. healthy donors (two groups total), which generated 16 discriminatory genes. They then selected genes that were shared across these highest discriminatory lists. Unless specifically noted as downregulated, all the genes in Table 17 are upregulated in MS. The genes already present in preferred list 1 are omitted.

[0051] While both the lists in Tables 16 and 17 provide preferred targets, other equally valuable lists, using different criteria (distinct patient populations, different types of MS, different age of onset, etc.) may be constructed.

[0052] 1. Discussion of Gene and Pathways Involved in MS

[0053] The following paragraphs represent a discussion of important pathways implicated in MS by the inventors' studies, and several key member molecules, found to be altered in MS peripheral blood by the inventors (see Tables above). Although the involvement of some of these genes might be inferred by in vitro or post-mortem experiments, there is very little in vivo evidence for most of these genes in MS. The present invention, which examines “immediately-ex vivo” material, is unique in approximating the in vivo setting, and provides far more conclusive evidence of their involvement.

[0054] Phosphatidylinositol transfer protein is upregulated in MS peripheral blood, and this protein serves as a lipid transport molecule (for membrane sphingolipids, for instance) and works at the interface of phospholipase c signaling and in membrane trafficking (including exocytosis and vesicle biogenesis). LERK-3 (EPLG3) is an ephrin-related receptor tyrosine kinase ligand that has been studied with relation to the nervous system but not to the immune system and has not been previously implicated in MS.

[0055] Several studies have implicated the nitric oxide (NO) pathway as a contributing factor in the pathogenesis of MS and of several other neurodegenerative or neuroinflammatory disorders. NO synthase leads to NO production, and NO reacts with superoxide anion to produce peroxynitrite (ONOO′). The stable end products of peroxynitrite (i.e., nitrite (NO2′) and nitrate (NO3′)) are commonly measured as an indirect evidence of NO-related oxidative damage. (Sarchielli et al., 1997) described higher production of nitrites in the supernatant of non-LPS-stimulated peripheral blood mononuclear cells of MS patients but only in patients with active lesions, or in patients undergoing disease relapses (also known as attacks or exacerbations). Others (Giovannoni et al. 1997) demonstrated elevated nitrite and nitrate in serum of patients with MS and in those with other neuro-inflammatory diseases, regardless of their level of disability. De Groot et al., 1997, has shown that in active MS lesions, there is strong iNOS immunoreactivity in perivascular and intralesional macrophages, indicating a possible role for this pathway in triggering cytotoxicity of oligodendrocytes and demyelination. Bagasra et al. (1995) also described high levels of iNOS in macrophages from MS postmortem brains. Bo et al., 1994, found iNOS mRNA elevation in demyelinating lesions of MS. Svenningsson et al. (1999), demonstrated increased nitrite levels in the cerebrospinal fluid (CSF) of MS patients with an active course. Yuceyar et al. (2001), found elevation of nitrate and nitrite in both serum and CSF of MS patients, independently of disease type, presence of exacerbation or degree of disability. Yamashita et al., (1997), demonstrated elevated CSF nitrate and nitrite at the most extreme stages of MS exacerbations. Liu et al. (2001), found higher expression of iNOS mRNA and protein in inflammatory cells and endothelial cells within early MS lesions, and in astrocytes at the edge of the lesion in chronic plaques. Lopez-Moratalla et al. (1997) demonstrated by immunocytochemistry and flow cytometry that iNOS was augmented in a subset (CD16+) of macrophages from peripheral blood. Importantly, Ding et al. (1998) has shown that using antisense oligodeoxynucleotides to specifically block the expression of iNOS in mice leads to resistance to the induction of experimental autoimmune encephalomyelitis (i.e., a disease induced in mice that represents the best known animal model of MS). Thus, DNA microarray experiments of peripheral blood detect mRNA changes that point towards potential targets of treatment, as exemplified by identification of iNOS elevation.

[0056] Bikunin represents the inhibitory light chain of the inter-α-trypsin inhibitor protein. It is a protease inhibitor, known to be elevated in the urine of patients with inflammatory diseases, such as psoriasis (Streit et al, 1995) and is considered an acute phase protein. However, there are no reports studying the role of bikunin in MS. The inventors reveal elevation of bikunin mRNA in MS suggesting that it is indeed a marker of inflammatory activity for this disease.

[0057] GATA-4 is a transcription factor that binds to genomic DNA containing GATA (genetic code) sequences. By itself, GATA-4 seems to be able to relax (decondense) compacted chromatin, suggesting a potential role in facilitating gene activation. It has been implicated in selectively upregulating interleukin 5, and may contribute to immune cell differentiation. Its role in immune cells to date is less understood than that of another family member, GATA-3, which is implicated in maintaining a Th2 (pro-humoral) T cell phenotype.

[0058] Thymopoietin is a thymic hormone and an immune modulator that is known to be upregulated by the action of transcription factors E2F-4 and E2F-1 (Ren et al., 2002). The inventors describe for the first time upregulation of thymopoietin RNA in peripheral blood of MS patients. Of interest, analogs of thymopoietin (i.e., thymopentin) have been devised in an attempt to treat autoimmunity. Kantharia et al. (1989), has shown that thymopentin ameliorates rheumatoid arthritis. It is unknown if the elevation of thymopoietin in peripheral blood of MS is a compensatory phenomenon.

[0059] The Rb-E2F pathway plays a central role in the ability of immune cells to progress through the cell cycle and proliferate (Wu et al., 2001). Surprisingly, there are no previous reports implicating this pathway in multiple sclerosis, as disease-related reports of this pathway focus on cancer. The inventors show detection of significant upregulation of E2F-2, E2F-3, E2F-5, Rb, CDC25A, CDK2, BCL2 and DNA primase (PRIMI) in peripheral blood of MS patients. The mRNA expression of Rb, CDC25A and even E2Fs themselves is known to be dependent on E2F-mediated transcription, suggesting that indeed E2Fs are primarily elevated in MS peripheral blood, and not secondarily elevated to compensate for dysregulation of other pathways. As mentioned, thymopoietin mRNA is also elevated in the peripheral blood of MS patients and is similarly dependent on E2Fs for its transcription. Also in support of an upregulated E2F pathway, multiple histone mRNAs (identified by the gene descriptions H4, H2B.1, H2A2, H3.1, and H3.3) are disclosed in this invention to be upregulated in MS peripheral blood mononuclear cells, and E2F transcription factors are known to induce the expression of histones. In addition, histone deacetylase 1 (HD1, also known as HDAC1), a global regulator known to bind Rb, was upregulated. None of these gene products have been previously demonstrated to be upregulated in MS peripheral blood. The inventors therefore sought to validate these novel findings in the murine experimental autoimmune encephalomyelitis (EAE) animal model of MS. The results (FIGS. 4A-C; Table 19) indicate a role in EAE for an activated E2F pathway, which plays an essential role in the ability of cells to progress through the cell cycle (Wu et al., 2001) and has been shown to play a role in autoimmunity (Murga et al., 2001) but had not previously been associated with MS. The findings suggest that E2f pathway-mediated cell cycle progression is required to mount a vigorous proliferation response to an antigenic challenge that leads to CNS autoimmunity.

TABLE 18
Clinical Findings
	EF21	Wild-Type	C57BL/6
Incidence	7/7	7/7	5/7
Day of Onset	14.9 ± 1.9	13.1 ± 0.9	12.8 ± 1.3
Mean Peak Remission Phase*	1.3 ± 0.2	2.5 ± 0.2	3 ± 0.2
Mean Percent Days of Severity*	6.8 ± 4.4	48.2 ± 7.5	59.5 ± 6.6
E2f1 deficient mice had a significant drop in the mean peak remission phase,
#defined as the mean of the maximal score reached during remission, and in the
#mean percentage of days of disease severity, defined as the mean % of days with
#scores ≧ 2 (* = P < 0.002 by Fisher's PLSD).

[0060] RNA polymerase II, required for transcriptional activity, and DNA topoisomerase III, involved in DNA replication and the maintenance of genomic stability, were upregulated in MS peripheral blood (not previously reported) suggesting enhanced transcriptional and cell division activity. The inventors disclosed the upregulated expression of cyclin C, which regulates proliferation via its interactions with RNA polymerase II (Rickert, 1996), and of cyclin D2, which enhances Rb phosphorylation, and therefore S phase cell cycle entry. The inventors also disclose enhanced expression in MS peripheral blood of the T cell receptor engagement-induced activation marker CD27, and soluble CD27 has been previously reported to be elevated in cerebrospinal fluid from MS patients (Hintzen et al., 1991). The inventors report that the hypoxanthine guanine phosphoribosyl transferase (HPRT) gene is downregulated in MS peripheral blood, and it has been shown that this gene accumulates mutations in immune cells undergoing repeated cell divisions, a likely a mechanism accompanying autoimmunity. In fact, mutations in HPRT (which would theoretically impair binding of the mutated target RNA to the probe sets on these chips) have been demonstrated in peripheral blood T cells that have expanded to react against myelin basic protein in MS patients (Allegreta et al., 1990). Thus, the lower detection of HPRT in MS may be due theoretically to a mutated (i.e., mismatched) target RNA. An important response to mutations or DNA damage would be to upregulate DNA repair genes, and the inventors disclose Rad23A homolog as an upregulated biomarker in MS. Surprisingly, hMLH1, another DNA repair gene product, is disclosed to be downregulated in MS peripheral blood. Further, O6-methylguanine-DNA methyltransferase, which removes mutagenic O6 alkylguanine from DNA, is hereby shown by the inventors to be strikingly downregulated in peripheral blood of MS. Aberrant DNA repair mechanisms may play a role in perpetuating autoimmunity, since proliferating cells tend to accumulate mutations, and the immune system is known to become progressively more and more dysregulated. In accordance with this concept, defective repair of O6-methyl guanine has been associated with autoimmune diseases such as arthritis and systemic lupus erythematosus (SLE) (Lawley et al., 1988).

[0061] Another important set of biomarkers for MS, not previously reported in association with this disease, include the upregulated retinoic acid pathway genes RXR β, RAR-β2, and RAR-γ1, possibly involved in immune cell differentiation. Another important aspect of the invention is the identification of several homeobox transcription factors that are dysregulated in MS (Gbx2, NBPhox, and Hox4D, all upregulated, and Hox3D, found to be downregulated). These transcription factors are highly conserved through evolution and have not previously been implicated in MS. As further support of the clonal expansion hypothesis, the inventors show multiple markers of T cell markers and T cell receptor genes that are upregulated in MS peripheral blood. These include: CD8 β chain glycoprotein, TCRBV1S1A1N1, T cell receptor clone IGRA17, T cell receptor β-chain J2.1, T-cell receptor active β-chain from Jurkat cell line, and T cell receptor zeta chain. As evidence of B cell clonal expansion, the inventors show specific immunoglobulin (Ig) gene transcripts and Ig receptors to be upregulated in MS, including: Ig J chain, Rearranged Ig lambda light chain, α β autoantibody IgM heavy chain variable V-D-J region, Ig-like transcript 2, Ig-like transcript 3, omega light chain Ig lambda light chain related, Ig heavy chain Vdjc region, IgG low affinity Fc fragment receptor (FcRIIa), and the leukocyte IgG receptor (Fc-γ-R).

[0062] The inventors also disclose the finding of multiple surface molecules that participate in cell-cell interactions and are known to lead to immune cell activation. These include: upregulated CD28, LFA-1, ICAM-2,4-1BB ligand, CD40 ligand, and importantly, downregulated CTLA4 (CD152), an immune attenuator that when knocked out in mice leads to autoimmunity. Several reports have already described the potential association of CTLA4, CD28, CD40 ligand and other costimulatory molecules (such as LFA-1) with autoimmunity. Signaling molecules are also disclosed, including vav and vav2, from a family of genes that mediate T- and B-cell receptor activation and influence NFkB and JNK signaling. Mice that carry mutations in cbl-b, a gene that interacts with vav, are prone to autoimmunity. Vav family members also mediate signaling from the Fe γ receptor IIa1, and a probe set for this immunoglobulin receptor was also upregulated in MS peripheral blood.

[0063] Further, complex survival pathway mechanisms for immune cells may play a role in autoimmunity, and the inventors describe their finding of upregulated Bcl-2, fas and fas ligand genes (all three previously implicated in MS), and downregulated survival motor neuron protein in the peripheral blood of MS patients. The inventors also disclose CLARP, a pro-apoptotic gene not previously associated with MS, as upregulated in peripheral blood.

[0064] Supporting clonal expansion and/or differentiation of immune cells, the following markers were found to be upregulated: T cell surface antigen CD2 (T11), B lymphocyte antigen CD20, myeloid cell nuclear differentiation antigen, GM-CSF receptor and macrophage colony stimulating factor (M-CSF), and the myeloid cell surface marker CD11b. Upregulation of class I molecules is also disclosed, including MHC class I (HLA-A*8001), MHC class I—C, MHC class I CD8 α chain, β-2 microglobulin, and the MHC binding protein 2 (MBP2). The acute phase reactant c-reactive protein was upregulated, and this gene product has not been previously implicated in MS. Several interleukins (IL) or IL-receptors were found to serve as biomarkers of MS, and included: chemokine IL-8 receptor β, IL-6 receptor, IL-16 protein precursor, IL-3 receptor α subunit, IL-7 receptor, and the TGF-βII receptor α. The IL-6 receptor soluble form (not its peripheral blood immune cell RNA counterpart) has been reported to be highly elevated in serum and CSF of MS patients (Padberg et al., 1999; Stelmasiak et al., 2001). The IL-8 receptor is a chemotactic receptor that has been demonstrated to be elevated within MS plaque macrophages (Muller-Ladner et al., 1996). Taken together, upregulated IL-3 receptor, E2Fs and Bcl-2(all involved in the same IL-3 pro-survival pathway) indicate a direct involvement in MS-related autoimmunity for these biomarkers.

[0065] A striking and unexpected disclosure in this invention is the upregulated expression of myelin genes in peripheral blood mononuclear cells. This has not been described before as a factor in autoimmunity affecting the central nervous system. Since myelin is known to be expressed in the central or peripheral nervous systems, or in the thymus, but not in peripheral blood, the inventors disclose the upregulated myelin-component genes 2,3-cyclic nucleotide 3 phosphodiesterase (CNP), myelin basic protein (MBP), myelin-associated oligodendrocytic basic protein (MOBP) as potential triggers of autoimmunity in the peripheral circulation (the first demonstration of their expression and upregulation in peripheral blood mononuclear cells) and as novel biomarkers of the disease. Further supporting this invention, the peripheral myelin protein PMP-22 was not upregulated in peripheral blood of MS patients. The findings are novel since these gene products have previously been hypothesized to trigger autoimmunity in humans from the central nervous system compartment, not from their upregulated expression in the peripheral circulation. Furthermore, butyrophilin, an antigen present in cow milk and therefore proposed as an environmental antigen though to lead to molecular mimicry in MS (Winer et al., 2001) and which localizes within the HLA/complement region in human chromosome 6, is found by the inventors to be elevated in peripheral blood of MS patients. In addition, the inventors demonstrate higher expression in MS blood of a transcript representing the putative MS autoantigen L neurofilament (Eikelenboom et al., 2003). The expression in the blood of these self antigens, whether present in differentiating hematopoietic precursors or in antigen presenting cells, may play a role in priming and maintaining the autoimmune response that leads to demyelination in MS, and may serve as targets of treatment.

[0066] In addition, it has been shown that activation of immune cells leads to aberrant expression of endogenous retroviral sequences (Johnston et al., 2001). Consistent with these reports, the inventors find specific upregulation of the probe sets representing human endogenous retrovirus K10 (HERVK10)/HUMMTV reverse transcriptase homolog, HERVK10 neutral protease protein, ERV9 reverse transcriptase homolog, and a tigger 1 transposable element. The inventors also show that an endogenous retrovirus probe set (X72790) is downregulated in MS patients receiving Avonex, suggesting a beneficial mechanism for the drug.

[0067] Further, several signaling molecules are disclosed as biomarkers of MS. These include several probe sets for each of the following: centaurin, casein kinase I, and PI3 kinase, known to participate in the same signaling pathway, among many other signaling molecules. Finally, the inventors disclose two signaling biomarkers in MS peripheral blood that may serve as targets of treatment: FK13P-rapamycin associated protein (FRAP), upregulated in MS, and Rapamycin and FK506-binding protein FKBPI3, found to be downregulated in MS peripheral blood.

[0068] Another biomarker reported by the inventors to be elevated in peripheral blood of MS patients is natural resistance-associated macrophage protein-1 (NRAMP1), a molecule involved in iron metabolism and in the susceptibility to infections and/or autoimmunity. NRAMP1 promoter allelic variation has been significantly associated with MS susceptibility in the South African Caucasian population (Kotze et al., 2001) but it has not been shown to be elevated in peripheral blood previously. The inventors also disclose upregulation in MS peripheral blood of the mRNAs for Calgizzarin, a calcium-binding protein also known as SiOOC, and for another probe set representing SiOOD, which have been implicated in the regulation of cytoskeletal function, suggesting that these proteins may participate in the morphological changes observed in activated immune cells. Neither calgizzarin nor S100D have been previously associated with MS in peripheral blood. A recent report described Calgizzarin (probe set D38583) elevation in MS brain lesions as demonstrated by DNA microarrays (Lock et al., 2002). Interestingly in that study Lock reported upregulation in MS brain tissue of several other genes that were also found to be upregulated in MS peripheral blood by the inventors. These include Stat5B (U47686) and obese (D49487) (both found to be upregulated in acute/active MS plaques by Lock), and T-cell receptor b-chain J2.1 gene (M14159), p38 mitogen activated protein (MAP) kinase (L35253, known to interact in the vav pathways), platelet glycoprotein IIa (GPIIIa) (M35999), and platelet glycoprotein IIb (GPIIb) (M34344) (all these found to be upregulated in chronic/silent MS plaques by Lock). In addition, other genes upregulated in peripheral blood of MS patients that are disclosed by the inventors, and were also found by Lock to be regulated in MS brain tissue included CDKIO (X78342), two lysozyme probe sets (X14008 and M19045), HSI hematopoietic lineage cell specific protein (X16663), heterogeneous nuder ribonucleoprotein I (Hnrp I) (X66975), 5′-nucleotidase (D38524), histone deacetylase 1 (HDAC1) (D50405), histone H2A.2 (L19779), hypothetical protein 384D8—7 (U62317) and a probe set for hypothetical protein A4 (U81556). Lock also reported multiple genes downregulated in MS brain tissue, some of which the inventors also disclose to be downregulated in peripheral blood of MS patients. These include: Thy-1 (M11749), Siah binding protein 1 (U51586), cytochrome c1 (J04444), and cytochrome c oxidase Va subunit (M22760). Finally, the cholecystokinin type A receptor (CCK-A) is a receptor previously implicated in pancreatic function and in the development of non-insulin dependent diabetes (Takiguchi et al., 1998), but not in MS: the inventors reveal its mRNA upregulation as a biomarker for multiple sclerosis.

[0069] Further supporting a role for oxidative stress in MS, the inventors have found that mitochondrial isocitrate dehydrogenase (NADP+) is downregulated in MS peripheral blood. Jo et al. (2001) have described an essential role for mitochondrial isocitrate dehydrogenase (NADP+) in preventing reactive oxygen species (ROS) generation. Therefore, this gene has potent antioxidant properties, and its downregulation in MS, in combination with elevated iNOS, may underlie oxidative stress-induced damage in this disease.

[0070] The inventors also demonstrate upregulation of the following genes in MS peripheral blood: the CUG repeat RNA-binding protein Etr-3 (probe set U69546), implicated in the regulation of splicing events (Ladd et al., 2001); the immunoglobulin superfamily member basal cell adhesion molecule (B-CAM); the adenomatous polyposis coli (APC) gene (represented in the microarray under the gene description “polyposis locus DP25”); a gene product known as LLGL (a regulatory target of the homeobox gene Hoxc8); the ubiquitin ligase cullin (CUL-2); the leukocyte antigen CD37, involved in regulating T cell-dependent B cell antibody responses (Knobeloch et al., 2000); and the ribosomal protein RPL37A. None of these biomarkers have previously been reported in association with MS.

[0071] KIAA0027 representing the membrane protein MLC1, KIAAOO10 representing an ubiquitin-protein isopeptide ligase, KIAA0128 representing septin 2, 6, and the KIAA0033 of yet unknown function, are also upregulated biomarkers for MS. In addition, probe sets representing uterus ficolin 1, nidogen (a basement membrane target of matrix metalloproteinases), the spliceosomal protein Sap62, the small G protein Gx, the G protein-coupled receptor v28, the transcription factor GATA-2 (probe set M68891) involved in immune cell differentiation, and the clone 23815 sequence (probe set U90916), are also disclosed as upregulated biomarkers for MS peripheral blood. In contrast, the α B-crystallin (a glioma Rosenthal fiber component) and the monocyte pseudoautosomal boundary mRNAs are both disclosed as downregulated biomarkers in MS peripheral blood mononuclear cells.

[0072] 2. Treatments

[0073] Multiple sclerosis is an inflammatory, autoimmune disease that is known to be adversely affected by interferon γ (i.e., administration to MS patients in a clinical study lead to disease exacerbations), but on the contrary, is benefited by treatment with interferon β. The inventors included in their study a population of MS patients on treatment with interferon-β (Avonex) as a control, to assess reliability of their invention. The inventors were able to identify in vivo, genes previously reported to respond to interferon β in vitro (Der et al., 1998; U.S. Pat. No. 6,331,396). For instance, in accordance with Der's report of in vitro-stimulated cells, the inventors showed that MS patients on treatment with interferon β have peripheral blood upregulation of the interferon-responsive genes LMP2 and IP-30, and downregulation of the known interferon-downregulatable gene histone H4. Of note, both histone H4 and E2F-3 are transcriptionally activated by E2F proteins, and MS patients on Avonex also had downregulated E2F-3 mRNA as compared to non-treated MS patients, suggesting that the Rb/E2F pathway may be a target of Avonex. The inventors also identified other genes known to be interferon pathway-related as upregulated in vivo (but not shown in Der's report), including the interferon regulatory factor 7A and the interferon γ-inducible indoleamine 23-dioxygenase. Further, the inventors showed multiple other genes that are shown to be up- or downregulated in patients receiving interferon β, indicating that they are targets of treatment as well.

[0074] Finally, the inventors identify four genes that were upregulated in MS peripheral blood, but not significantly downregulated in vivo by Avonex; however, they may still represent valid targets of interferon β since it is now known that other commercial versions of interferon β may be more efficacious in vivo (i.e., Rebif and Betaseron), and they are shown in Der's report to be downregulated by interferon β but not by interferon γ. These four genes are clone Id2, ZnT-3, clone 23748, and a gene represented by accession number U82311. The inventors therefore disclose these genes specifically as therapeutic targets in MS.

[0075] III. Diagnostic/Prognostic Determinations in MS

[0076] The lists presented above can be used for determination of sample origin (ALS/healthy vs. MS). The lists above (except for Table 16) were generated by comparing the gene expression profile of peripheral blood mononuclear cells derived from 5 relapsing-remitting MS patients, 5 relapsing-remitting MS patients on treatment with Avonex (IFN-β1a), 5 ALS patients, and 5 healthy donors. As expected, the comparison of ALS vs. healthy donors yielded no significant differences, since ALS is not an autoimmune disease. However, every comparison involving MS patients peripheral blood yielded massive changes in gene expression, consistent with its autoimmune nature. The gene expression changes were separated into three classes:

[0077] (1) highest discriminatory, having a P value <0.05 by a new statistical method (see examples), regardless of the P value by T statistics (a much less stringent method);

[0078] (2) intermediate discriminatory: P value <0.01 by T statistics and >0.05 by the new method; and

[0079] (3) least discriminatory: P value <0.05 by T statistics and >0.05 by the new method.

[0080] Note that the least discriminatory genes may also be used for diagnostic purposes using microarrays or other methods (see below). In addition, since ALS samples did not differ in any significant manner from healthy donor samples, the gene lists in which both ALS and healthy donors are combined into a single group (to provide higher statistical validity) compared to MS are preferred in this invention for demonstrating MS discriminatory genes.

[0081] IV. Methods of Assaying for Alterations in Gene Expression

[0082] Thus, in accordance with the present invention, methods are provided for the assaying of gene expression in patients suffering from or at risk of MS. As discussed above, the principal applications of this assay are to: (a) identify patients whose gene expression profile puts them at risk of developing MS; identify patients whose symptoms are such that they may or may not be suffering from MS (i.e., provide a definitive diagnosis of MS); and (c) assess the impact of an MS therapy. In each of these assays, the expression of a particular set of genes, set forth in the preceding sections, will be measured. The following is a discussion of various aspects of these methods.

[0083] 1. Hybridization

[0084] There are a variety of ways by which one can assess gene expression. These methods either look at protein or at mRNA levels. Methods looking at mRNAs all fundamentally rely, at a basic level, on nucleic acid hybridization. Hybridization is defined as the ability of a nucleic acid to selectively form duplex molecules with complementary stretches of DNAs and/or RNAs. Depending on the application envisioned, one would employ varying conditions of hybridization to achieve varying degrees of selectivity of the probe or primers for the target sequence.

[0085] Typically, a probe or primer of between 13 and 100 nucleotides, preferably between 17 and 100 nucleotides in length up to 1-2 kilobases or more in length will allow the formation of a duplex molecule that is both stable and selective. Molecules having complementary sequences over contiguous stretches greater than 20 bases in length are generally preferred, to increase stability and selectivity of the hybrid molecules obtained. One will generally prefer to design nucleic acid molecules for hybridization having one or more complementary sequences of 20 to 30 nucleotides, or even longer where desired. Such fragments may be readily prepared, for example, by directly synthesizing the fragment by chemical means or by introducing selected sequences into recombinant vectors for recombinant production.

[0086] For applications requiring high selectivity, one will typically desire to employ relatively high stringency conditions to form the hybrids. For example, relatively low salt and/or high temperature conditions, such as provided by about 0.02 M to about 0.10 M NaCl at temperatures of about 50° C. to about 70° C. Such high stringency conditions tolerate little, if any, mismatch between the probe or primers and the template or target strand and would be particularly suitable for isolating specific genes or for detecting specific mRNA transcripts. It is generally appreciated that conditions can be rendered more stringent by the addition of increasing amounts of formamide.

[0087] For certain applications, for example, lower stringency conditions may be used. Under these conditions, hybridization may occur even though the sequences of the hybridizing strands are not perfectly complementary, but are mismatched at one or more positions. Conditions may be rendered less stringent by increasing salt concentration and/or decreasing temperature. For example, a medium stringency condition could be provided by about 0.1 to 0.25 M NaCl at temperatures of about 37° C. to about 55° C., while a low stringency condition could be provided by about 0.15 M to about 0.9 M salt, at temperatures ranging from about 20° C. to about 55° C. Hybridization conditions can be readily manipulated depending on the desired results.

[0088] In other embodiments, hybridization may be achieved under conditions of, for example, 50 mM Tris-HCl (pH 8.3), 75 mM KCl, 3 mM MgCl2, 1.0 mM dithiothreitol, at temperatures between approximately 20° C. to about 37° C. Other hybridization conditions utilized could include approximately 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, at temperatures ranging from approximately 40° C. to about 72° C.

[0089] In certain embodiments, it will be advantageous to employ nucleic acids of defined sequences of the present invention in combination with an appropriate means, such as a label, for determining hybridization. A wide variety of appropriate indicator means are known in the art, including fluorescent, radioactive, enzymatic or other ligands, such as avidin/biotin, which are capable of being detected. In preferred embodiments, one may desire to employ a fluorescent label or an enzyme tag such as urease, alkaline phosphatase or peroxidase, instead of radioactive or other environmentally undesirable reagents. In the case of enzyme tags, colorimetric indicator substrates are known that can be employed to provide a detection means that is visibly or spectrophotometrically detectable, to identify specific hybridization with complementary nucleic acid containing samples.

[0090] In general, it is envisioned that the probes or primers described herein will be useful as reagents in solution hybridization, as in PCRTM, for detection of expression of corresponding genes, as well as in embodiments employing a solid phase. In embodiments involving a solid phase, the test DNA (or RNA) is adsorbed or otherwise affixed to a selected matrix or surface. This fixed, single-stranded nucleic acid is then subjected to hybridization with selected probes under desired conditions. The conditions selected will depend on the particular circumstances (depending, for example, on the G+C content, type of target nucleic acid, source of nucleic acid, size of hybridization probe, etc.). Optimization of hybridization conditions for the particular application of interest is well known to those of skill in the art. After washing of the hybridized molecules to remove non-specifically bound probe molecules, hybridization is detected, and/or quantified, by determining the amount of bound label. Representative solid phase hybridization methods are disclosed in U.S. Pat. Nos. 5,843,663, 5,900,481 and 5,919,626. Other methods of hybridization that may be used in the practice of the present invention are disclosed in U.S. Pat. Nos. 5,849,481, 5,849,486 and 5,851,772. The relevant portions of these and other references identified in this section of the Specification are incorporated herein by reference.

[0091] 2. Amplification of Nucleic Acids

[0092] Since many nucleic acids, especially mRNAs, are in low abundance, nucleic acid amplification greatly enhances the ability to assess expression. The general concept is that nucleic acids can be amplified using paired primers flanking the region of interest. The term “primer,” as used herein, is meant to encompass any nucleic acid that is capable of priming the synthesis of a nascent nucleic acid in a template-dependent process. Typically, primers are oligonucleotides from ten to twenty and/or thirty base pairs in length, but longer sequences can be employed. Primers may be provided in double-stranded and/or single-stranded form, although the single-stranded form is preferred.

[0093] Pairs of primers designed to selectively hybridize to nucleic acids corresponding to selected genes are contacted with the template nucleic acid under conditions that permit selective hybridization. Depending upon the desired application, high stringency hybridization conditions may be selected that will only allow hybridization to sequences that are completely complementary to the primers. In other embodiments, hybridization may occur under reduced stringency to allow for amplification of nucleic acids containing one or more mismatches with the primer sequences. Once hybridized, the template-primer complex is contacted with one or more enzymes that facilitate template-dependent nucleic acid synthesis. Multiple rounds of amplification, also referred to as “cycles,” are conducted until a sufficient amount of amplification product is produced.

[0094] The amplification product may be detected or quantified. In certain applications, the detection may be performed by visual means. Alternatively, the detection may involve indirect identification of the product via chemilluminescence, radioactive scintigraphy of incorporated radiolabel or fluorescent label or even via a system using electrical and/or thermal impulse signals.

[0095] A number of template dependent processes are available to amplify the oligonucleotide sequences present in a given template sample. One of the best known amplification methods is the polymerase chain reaction (referred to as PCRTM) which is described in detail in U.S. Pat. Nos. 4,683,195, 4,683,202 and 4,800,159, and in Innis et al., 1988, each of which is incorporated herein by reference in their entirety.

[0096] A reverse transcriptase PCR™ amplification procedure may be performed to quantify the amount of mRNA amplified. Methods of reverse transcribing RNA into cDNA are well known (see Sambrook et al., 1989). Alternative methods for reverse transcription utilize thermostable DNA polymerases. These methods are described in WO 90/07641. Polymerase chain reaction methodologies are well known in the art. Representative methods of RT-PCR are described in U.S. Pat. No. 5,882,864.

[0097] Whereas standard PCR usually uses one pair of primers to amplify a specific sequence, multiplex-PCR (MPCR) uses multiple pairs of primers to amplify many sequences simultaneously (Chamberlan et al., 1990). The presence of many PCR primers in a single tube could cause many problems, such as the increased formation of misprimed PCR products and “primer dimers”, the amplification discrimination of longer DNA fragment and so on. Normally, MPCR buffers contain a Taq Polymerase additive, which decreases the competition among amplicons and the amplification discrimination of longer DNA fragment during MPCR. MPCR products can further be hybridized with gene-specific probe for verification. Theoretically, one should be able to use as many as primers as necessary. However, due to side effects (primer dimers, misprimed PCR products, etc.) caused during MPCR, there is a limit (less than 20) to the number of primers that can be used in a MPCR reaction. See also European Application No. 0 364 255 and Mueller and Wold (1989).

[0098] Another method for amplification is ligase chain reaction (“LCR”), disclosed in European Application No. 320 308, incorporated herein by reference in its entirety. U.S. Pat. No. 4,883,750 describes a method similar to LCR for binding probe pairs to a target sequence. A method based on PCR™ and oligonucleotide ligase assay (OLA), disclosed in U.S. Pat. No. 5,912,148, may also be used.

[0099] Alternative methods for amplification of target nucleic acid sequences that may be used in the practice of the present invention are disclosed in U.S. Pat. Nos. 5,843,650, 5,846,709, 5,846,783, 5,849,546, 5,849,497, 5,849,547, 5,858,652, 5,866,366, 5,916,776, 5,922,574, 5,928,905, 5,928,906, 5,932,451, 5,935,825, 5,939,291 and 5,942,391, GB Application No. 2 202 328, and in PCT Application No. PCT/US89/01025, each of which is incorporated herein by reference in its entirety.

[0100] Qbeta Replicase, described in PCT Application No. PCT/US87/00880, may also be used as an amplification method in the present invention. In this method, a replicative sequence of RNA that has a region complementary to that of a target is added to a sample in the presence of an RNA polymerase. The polymerase will copy the replicative sequence which may then be detected.

[0101] An isothermal amplification method, in which restriction endonucleases and ligases are used to achieve the amplification of target molecules that contain nucleotide 5′-[α-thio]-triphosphates in one strand of a restriction site may also be useful in the amplification of nucleic acids in the present invention (Walker et al., 1992). Strand Displacement Amplification (SDA), disclosed in U.S. Pat. No. 5,916,779, is another method of carrying out isothermal amplification of nucleic acids which involves multiple rounds of strand displacement and synthesis, i.e., nick translation.

[0102] Other nucleic acid amplification procedures include transcription-based amplification systems (TAS), including nucleic acid sequence based amplification (NASBA) and 3SR (Kwoh et al., 1989; Gingeras et al., PCT Application WO 88/10315, incorporated herein by reference in their entirety). European Application No. 329 822 disclose a nucleic acid amplification process involving cyclically synthesizing single-stranded RNA (“ssRNA”), ssDNA, and double-stranded DNA (dsDNA), which may be used in accordance with the present invention.

[0103] PCT Application WO 89/06700 (incorporated herein by reference in its entirety) disclose a nucleic acid sequence amplification scheme based on the hybridization of a promoter region/primer sequence to a target single-stranded DNA (“ssDNA”) followed by transcription of many RNA copies of the sequence. This scheme is not cyclic, i.e., new templates are not produced from the resultant RNA transcripts. Other amplification methods include “race” and “one-sided PCR” (Frohiman, 1990; Ohara et al., 1989).

[0104] 3. Detection of Nucleic Acids

[0105] Following any amplification, it may be desirable to separate the amplification product from the template and/or the excess primer. In one embodiment, amplification products are separated by agarose, agarose-acrylamide or polyacrylamide gel electrophoresis using standard methods (Sambrook et al., 1989). Separated amplification products may be cut out and eluted from the gel for further manipulation. Using low melting point agarose gels, the separated band may be removed by heating the gel, followed by extraction of the nucleic acid.

[0106] Separation of nucleic acids may also be effected by chromatographic techniques known in art. There are many kinds of chromatography which may be used in the practice of the present invention, including adsorption, partition, ion-exchange, hydroxylapatite, molecular sieve, reverse-phase, column, paper, thin-layer, and gas chromatography as well as HPLC.

[0107] In certain embodiments, the amplification products are visualized. A typical visualization method involves staining of a gel with ethidium bromide and visualization of bands under UV light. Alternatively, if the amplification products are integrally labeled with radio- or fluorometrically-labeled nucleotides, the separated amplification products can be exposed to x-ray film or visualized under the appropriate excitatory spectra.

[0108] In one embodiment, following separation of amplification products, a labeled nucleic acid probe is brought into contact with the amplified marker sequence. The probe preferably is conjugated to a chromophore but may be radiolabeled. In another embodiment, the probe is conjugated to a binding partner, such as an antibody or biotin, or another binding partner carrying a detectable moiety.

[0109] In particular embodiments, detection is by Southern blotting and hybridization with a labeled probe. The techniques involved in Southern blotting are well known to those of skill in the art (see Sambrook et al., 1989). One example of the foregoing is described in U.S. Pat. No. 5,279,721, incorporated by reference herein, which discloses an apparatus and method for the automated electrophoresis and transfer of nucleic acids. The apparatus permits electrophoresis and blotting without external manipulation of the gel and is ideally suited to carrying out methods according to the present invention.

[0110] Other methods of nucleic acid detection that may be used in the practice of the instant invention are disclosed in U.S. Pat. Nos. 5,840,873, 5,843,640, 5,843,651, 5,846,708, 5,846,717, 5,846,726, 5,846,729, 5,849,487, 5,853,990, 5,853,992, 5,853,993, 5,856,092, 5,861,244, 5,863,732, 5,863,753, 5,866,331, 5,905,024, 5,910,407, 5,912,124, 5,912,145, 5,919,630, 5,925,517, 5,928,862, 5,928,869, 5,929,227, 5,932,413 and 5,935,791, each of which is incorporated herein by reference.

[0111] 4. Nucleic Acid Arrays

[0112] Microarrays comprise a plurality of polymeric molecules spatially distributed over, and stably associated with, the surface of a substantially planar substrate, e.g., biochips. Microarrays of polynucleotides have been developed and find use in a variety of applications, such as screening and DNA sequencing. One area in particular in which microarrays find use is in gene expression analysis.

[0113] In gene expression analysis with microarrays, an array of “probe” oligonucleotides is contacted with a nucleic acid sample of interest, i.e., target, such as polyA mRNA or total RNA from a particular tissue type. Contact is carried out under hybridization conditions and unbound nucleic acid is then removed. The resultant pattern of hybridized nucleic acid provides information regarding the genetic profile of the sample tested. Methodologies of gene expression analysis on microarrays are capable of providing both qualitative and quantitative information.

[0114] A variety of different arrays which may be used are known in the art. The probe molecules of the arrays which are capable of sequence specific hybridization with target nucleic acid may be polynucleotides or hybridizing analogues or mimetics thereof, including: nucleic acids in which the phosphodiester linkage has been replaced with a substitute linkage, such as phophorothioate, methylimino, methylphosphonate, phosphoramidate, guanidine and the like; nucleic acids in which the ribose subunit has been substituted, e.g., hexose phosphodiester; peptide nucleic acids; and the like. The length of the probes will generally range from 10 to 1000 nts, where in some embodiments the probes will be oligonucleotides and usually range from 15 to 150 nts and more usually from 15 to 100 nts in length, and in other embodiments the probes will be longer, usually ranging in length from 150 to 1000 nts, where the polynucleotide probes may be single- or double-stranded, usually single-stranded, and may be PCR fragments amplified from cDNA.

[0115] The probe molecules on the surface of the substrates will correspond to selected genes being analyzed and be positioned on the array at a known location so that positive hybridization events may be correlated to expression of a particular gene in the physiological source from which the target nucleic acid sample is derived. The substrates with which the probe molecules are stably associated may be fabricated from a variety of materials, including plastics, ceramics, metals, gels, membranes, glasses, and the like. The arrays may be produced according to any convenient methodology, such as preforming the probes and then stably associating them with the surface of the support or growing the probes directly on the support. A number of different array configurations and methods for their production are known to those of skill in the art and disclosed in U.S. Pat. Nos. 5,445,934, 5,532,128, 5,556,752, 5,242,974, 5,384,261, 5,405,783, 5,412,087, 5,424,186, 5,429,807, 5,436,327, 5,472,672, 5,527,681, 5,529,756, 5,545,531, 5,554,501,5,561,071, 5,571,639, 5,593,839, 5,599,695, 5,624,711, 5,658,734, 5,700,637, and 6,004,755.

[0116] Following hybridization, where non-hybridized labeled nucleic acid is capable of emitting a signal during the detection step, a washing step is employed where unhybridized labeled nucleic acid is removed from the support surface, generating a pattern of hybridized nucleic acid on the substrate surface. A variety of wash solutions and protocols for their use are known to those of skill in the art and may be used.

[0117] Where the label on the target nucleic acid is not directly detectable, one then contacts the array, now comprising bound target, with the other member(s) of the signal producing system that is being employed. For example, where the label on the target is biotin, one then contacts the array with streptavidin-fluorescer conjugate under conditions sufficient for binding between the specific binding member pairs to occur. Following contact, any unbound members of the signal producing system will then be removed, e.g., by washing. The specific wash conditions employed will necessarily depend on the specific nature of the signal producing system that is employed, and will be known to those of skill in the art familiar with the particular signal producing system employed.

[0118] The resultant hybridization pattern(s) of labeled nucleic acids may be visualized or detected in a variety of ways, with the particular manner of detection being chosen based on the particular label of the nucleic acid, where representative detection means include scintillation counting, autoradiography, fluorescence measurement, calorimetric measurement, light emission measurement and the like.

[0119] Prior to detection or visualization, where one desires to reduce the potential for a mismatch hybridization event to generate a false positive signal on the pattern, the array of hybridized target/probe complexes may be treated with an endonuclease under conditions sufficient such that the endonuclease degrades single stranded, but not double stranded DNA. A variety of different endonucleases are known and may be used, where such nucleases include: mung bean nuclease, S1 nuclease, and the like. Where such treatment is employed in an assay in which the target nucleic acids are not labeled with a directly detectable label, e.g., in an assay with biotinylated target nucleic acids, the endonuclease treatment will generally be performed prior to contact of the array with the other member(s) of the signal producing system, e.g., fluorescent-streptavidin conjugate. Endonuclease treatment, as described above, ensures that only end-labeled target/probe complexes having a substantially complete hybridization at the 3′ end of the probe are detected in the hybridization pattern.

[0120] Following hybridization and any washing step(s) and/or subsequent treatments, as described above, the resultant hybridization pattern is detected. In detecting or visualizing the hybridization pattern, the intensity or signal value of the label will be not only be detected but quantified, by which is meant that the signal from each spot of the hybridization will be measured and compared to a unit value corresponding the signal emitted by known number of end-labeled target nucleic acids to obtain a count or absolute value of the copy number of each end-labeled target that is hybridized to a particular spot on the array in the hybridization pattern.

[0121] V. Protein-Based Diagnostic Assays

[0122] In another aspects of the invention, one may employ a protein-based diagnostic approach. The most common form of protein identification is by the use of antibodies. As used herein, the term “antibody” is intended to refer broadly to any immunologic binding agent such as IgG, IgM, IgA, IgD and IgE. Generally, IgG and/or IgM are preferred because they are the most common antibodies in the physiological situation and because they are most easily made in a laboratory setting. The term “antibody” also refers to any antibody-like molecule that has an antigen binding region, and includes antibody fragments such as Fab′, Fab, F(ab′)2, single domain antibodies (DABs), Fv, scFv (single chain Fv), and the like. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art. Means for preparing and characterizing antibodies, both polyclonal and monoclonal, are also well known in the art (See, e.g., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988; incorporated herein by reference).

[0123] In accordance with the present invention, immunodetection methods are provided. Some immunodetection methods include enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoradiometric assay, fluoroimmunoassay, chemiluminescent assay, bioluminescent assay, and Western blot to mention a few. The steps of various useful immunodetection methods have been described in the scientific literature, such as, e.g., Doolittle and Ben-Zeev 0, 1999; Gulbis and Galand, 1993; De Jager et al., 1993; and Nakamura et al., 1987, each incorporated herein by reference.

[0124] In general, the immunobinding methods include obtaining a sample suspected of containing a relevant polypeptide, and contacting the sample with a first antibody under conditions effective to allow the formation of immunocomplexes. In terms of antigen detection, the biological sample analyzed may be any sample that is suspected of containing an antigen, such as, for example, a tissue section or specimen, a homogenized tissue extract, a cell, or even a biological fluid.

[0125] Contacting the chosen biological sample with the antibody under effective conditions and for a period of time sufficient to allow the formation of immune complexes (primary immune complexes) is generally a matter of simply adding the antibody composition to the sample and incubating the mixture for a period of time long enough for the antibodies to form immune complexes with, i.e., to bind to, any antigens present. After this time, the sample-antibody composition, such as a tissue section, ELISA plate, dot blot or western blot, will generally be washed to remove any non-specifically bound antibody species, allowing only those antibodies specifically bound within the primary immune complexes to be detected.

[0126] In general, the detection of immunocomplex formation is well known in the art and may be achieved through the application of numerous approaches. These methods are generally based upon the detection of a label or marker, such as any of those radioactive, fluorescent, biological and enzymatic tags. U.S. patents concerning the use of such labels include U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149 and 4,366,241, each incorporated herein by reference. Of course, one may find additional advantages through the use of a secondary binding ligand such as a second antibody and/or a biotin/avidin ligand binding arrangement, as is known in the art.

[0127] The antibody employed in the detection may itself be linked to a detectable label, wherein one would then simply detect this label, thereby allowing the amount of the primary immune complexes in the composition to be determined. Alternatively, the first antibody that becomes bound within the primary immune complexes may be detected by means of a second binding ligand that has binding affinity for the antibody. In these cases, the second binding ligand may be linked to a detectable label. The second binding ligand is itself often an antibody, which may thus be termed a “secondary” antibody. The primary immune complexes are contacted with the labeled, secondary binding ligand, or antibody, under effective conditions and for a period of time sufficient to allow the formation of secondary immune complexes. The secondary immune complexes are then generally washed to remove any non-specifically bound labeled secondary antibodies or ligands, and the remaining label in the secondary immune complexes is then detected.

[0128] Further methods include the detection of primary immune complexes by a two step approach. A second binding ligand, such as an antibody, that has binding affinity for the antibody is used to form secondary immune complexes, as described above. After washing, the secondary immune complexes are contacted with a third binding ligand or antibody that has binding affinity for the second antibody, again under effective conditions and for a period of time sufficient to allow the formation of immune complexes (tertiary immune complexes). The third ligand or antibody is linked to a detectable label, allowing detection of the tertiary immune complexes thus formed. This system may provide for signal amplification if this is desired.

[0129] One method of immunodetection designed by Charles Cantor uses two different antibodies. A first step biotinylated, monoclonal or polyclonal antibody is used to detect the target antigen(s), and a second step antibody is then used to detect the biotin attached to the complexed biotin. In that method the sample to be tested is first incubated in a solution containing the first step antibody. If the target antigen is present, some of the antibody binds to the antigen to form a biotinylated antibody/antigen complex. The antibody/antigen complex is then amplified by incubation in successive solutions of streptavidin (or avidin), biotinylated DNA, and/or complementary biotinylated DNA, with each step adding additional biotin sites to the antibody/antigen complex. The amplification steps are repeated until a suitable level of amplification is achieved, at which point the sample is incubated in a solution containing the second step antibody against biotin. This second step antibody is labeled, as for example with an enzyme that can be used to detect the presence of the antibody/antigen complex by histoenzymology using a chromogen substrate. With suitable amplification, a conjugate can be produced which is macroscopically visible.

[0130] Another known method of immunodetection takes advantage of the immuno-PCR (Polymerase Chain Reaction) methodology. The PCR method is similar to the Cantor method up to the incubation with biotinylated DNA, however, instead of using multiple rounds of streptavidin and biotinylated DNA incubation, the DNA/biotin/streptavidin/antibody complex is washed out with a low pH or high salt buffer that releases the antibody. The resulting wash solution is then used to carry out a PCR reaction with suitable primers with appropriate controls. At least in theory, the enormous amplification capability and specificity of PCR can be utilized to detect a single antigen molecule.

[0131] As detailed above, immunoassays are in essence binding assays. Certain immunoassays are the various types of enzyme linked immunosorbent assays (ELISAs) and radioimmunoassays (RIA) known in the art. However, it will be readily appreciated that detection is not limited to such techniques, and Western blotting, dot blotting, FACS analyses, and the like may also be used.

[0132] In one exemplary ELISA, the antibodies of the invention are immobilized onto a selected surface exhibiting protein affinity, such as a well in a polystyrene microtiter plate. Then, a test composition suspected of containing the antigen, such as a clinical sample, is added to the wells. After binding and washing to remove non-specifically bound immune complexes, the bound antigen may be detected. Detection is generally achieved by the addition of another antibody that is linked to a detectable label. This type of ELISA is a simple “sandwich ELISA”. Detection may also be achieved by the addition of a second antibody, followed by the addition of a third antibody that has binding affinity for the second antibody, with the third antibody being linked to a detectable label.

[0133] In another exemplary ELISA, the samples suspected of containing the antigen are immobilized onto the well surface and then contacted with the anti-ORF message and anti-ORF translated product antibodies of the invention. After binding and washing to remove nonspecifically bound immune complexes, the bound anti-ORF message and anti-ORF translated product antibodies are detected. Where the initial anti-ORF message and anti-ORF translated product antibodies are linked to a detectable label, the immune complexes may be detected directly. Again, the immune complexes may be detected using a second antibody that has binding affinity for the first anti-ORF message and anti-ORF translated product antibody, with the second antibody being linked to a detectable label.

[0134] Another ELISA in which the antigens are immobilized, involves the use of antibody competition in the detection. In this ELISA, labeled antibodies against an antigen are added to the wells, allowed to bind, and detected by means of their label. The amount of an antigen in an unknown sample is then determined by mixing the sample with the labeled antibodies against the antigen during incubation with coated wells. The presence of an antigen in the sample acts to reduce the amount of antibody against the antigen available for binding to the well and thus reduces the ultimate signal. This is also appropriate for detecting antibodies against an antigen in an unknown sample, where the unlabeled antibodies bind to the antigen-coated wells and also reduces the amount of antigen available to bind the labeled antibodies. “Under conditions effective to allow immune complex (antigen/antibody) formation” means that the conditions preferably include diluting the antigens and/or antibodies with solutions such as BSA, bovine ≡ globulin (BGG) or phosphate buffered saline (PBS)/Tween. These added agents also tend to assist in the reduction of nonspecific background. The “suitable” conditions also mean that the incubation is at a temperature or for a period of time sufficient to allow effective binding. Incubation steps are typically from about 1 to 2 to 4 hours or so, at temperatures preferably on the order of 25° C. to 27° C., or may be overnight at about 4° C. or so.

[0135] The antibodies of the present invention may also be used in conjunction with both fresh-frozen and/or formalin-fixed, paraffin-embedded tissue blocks prepared for study by immunohistochemistry (IHC). The method of preparing tissue blocks from these particulate specimens has been successfully used in previous IHC studies of various prognostic factors, and/or is well known to those of skill in the art (Brown et al., 1990; Abbondanzo et al., 1999; Allred et al., 1990).

[0136] Also contemplated in the present invention is the use of immunohistochemistry. This approach uses antibodies to detect and quantify antigens in intact tissue samples. Generally, frozen-sections are prepared by rehydrating frozen “pulverized” tissue at room temperature in phosphate buffered saline (PBS) in small plastic capsules; pelleting the particles by centrifugation; resuspending them in a viscous embedding medium (OCT); inverting the capsule and pelleting again by centrifugation; snap-freezing in −70° C. isopentane; cutting the plastic capsule and removing the frozen cylinder of tissue; securing the tissue cylinder on a cryostat microtome chuck; and cutting 25-50 serial sections.

[0137] Permanent-sections may be prepared by a similar method involving rehydration of the 50 mg sample in a plastic microfuge tube; pelleting; resuspending in 10% formalin for 4 hours fixation; washing/pelleting; resuspending in warm 2.5% agar; pelleting; cooling in ice water to harden the agar; removing the tissue/agar block from the tube; infiltrating and/or embedding the block in paraffin; and cutting up to 50 serial permanent sections.

[0138] VI. Gene Therapy

[0139] In another embodiment, the present invention provides for the administration of a gene therapy vector encoding one or more genes identified as being downregulated in MS. Alternatively, for genes that are overexpressed in MS, the transgenes may provide for reduced expression of appropriate targets. Various aspects of gene delivery and expression are set forth below.

[0140] 1. Therapeutic Transgenes

[0141] Thus, in accordance with the present invention, there are provided methods of treating MS utilizing genes identified as being overexpressed or underexpressed in MS. By inhibiting or increasing the expression of various of these genes, therapeutic benefit may be provided to patients.

[0142] 2. Antisense

[0143] The term “antisense” nucleic acid refers to oligo- and polynucleotides complementary to bases sequences of a target DNA or RNA. When introduced into a cell, antisense molecules hybridize to a target nucleic acid and interfere with its transcription, transport, processing, splicing or translation. Targeting double-stranded DNA leads to triple helix formation; targeting RNA will lead to double helix formation.

[0144] Antisense constructs may be designed to bind to the promoter or other control regions, exons, introns or even exon-intron boundaries of a gene. Antisense RNA constructs, or DNA encoding such antisense RNA's, may be employed to inhibit gene transcription or translation within a host cell. Nucleic acid sequences which comprise “complementary nucleotides” are those which are capable of base-pairing according to the standard Watson-Crick complementarity rules. That is, that the larger purines will base pair with the smaller pyrimidines to form combinations of guanine paired with cytosine (G:C) and adenine paired with either thymine in the case of DNA (A:T), or uracil (A:U) in the case of RNA. Inclusion of less common bases such as inosine, 5-methylcytosine, 6-methyladenine, hypoxanthine and others in hybridizing sequences does not interfere with pairing.

[0145] As used herein, the terms “complementary” and “antisense sequences” mean nucleic acid sequences that are substantially complementary over their entire length and have very few base mismatches. For example, nucleic acid sequences of fifteen bases in length may be termed complementary when they have complementary nucleotides at thirteen or fourteen positions. Naturally, nucleic acid sequences with are “completely complementary” will be nucleic acid sequences which have perfect base pair matching with the target sequences, i.e., no mismatches. Other sequences with lower degrees of homology are contemplated. For example, an antisense construct with limited regions of high homology, but overall containing a lower degree (50% or less) total homology, may be used.

[0146] While all or part of the gene sequence may be employed in the context of antisense construction, statistically, any sequence of 17 bases long should occur only once in the human genome and, therefore, suffice to specify a unique target. Although shorter oligomers are easier to make and increase in vivo accessibility, numerous other factors are involved in determining the specificity of hybridization: Both binding affinity and sequence specificity of an oligonucleotide to its complementary target increases with increasing length. It is contemplated that oligonucleotides of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more base pairs will be used. One can readily determine whether a given antisense nucleic acid is effective at targeting a gene simply by testing the construct in vitro to determine whether the gene's function or expression is affected.

[0147] In certain embodiments, one may wish to employ antisense constructs which include other elements, for example, those which include C-5 propyne pyrimidines. Oligonucleotides which contain C-5 propyne analogs of uridine and cytidine have been shown to bind RNA with high affinity and to be potent inhibitors or gene expression. Wagner et al. (1993).

[0148] 3. Ribozymes

[0149] The term “ribozyme” refers to an RNA-based enzyme capable of targeting and cleaving particular DNA and RNA sequences. Ribozymes can either be targeted directly to cells, in the form of RNA oligonucleotides incorporating ribozyme sequences, or introduced into the cell as an expression construct encoding the desired ribozymal RNA. Ribozymes may be used and applied in much the same way as described for antisense nucleic acids. Ribozyme sequences also may be modified in much the same way as described for antisense nucleic acids. For example, one could include modified bases or modified phosphate backbones to improve stability or function.

[0150] 4. RNA Interference

[0151] RNA interference (RNAi) is a form of gene silencing triggered by double-stranded RNA (dsRNA). DsRNA activates post-transcriptional gene expression surveillance mechanisms that appear to function to defend cells from virus infection and transposon activity. Fire et al. (1998); Grishok et al. (2000); Ketting et al. (1999); Lin & Avery (1999); Montgomery et al. (1998); Sharp (1999); Sharp & Zamore (2000); Tabara et al. (1999). Activation of these mechanisms targets mature, dsRNA-complementary mRNA for destruction. RNAi offers major experimental advantages for study of gene function. These advantages include a very high specificity, ease of movement across cell membranes, and prolonged down-regulation of the targeted gene. Fire et al. (1998); Grishok et al. (2000); Ketting et al. (1999); Lin & Avery (1999); Montgomery et al. (1998); Sharp (1999); Sharp & Zamore (2000); Tabara et al. (1999). Moreover, dsRNA has been shown to silence genes in a wide range of systems, including plants, protozoans, fungi, C. elegans, Trypanosoma and Drosophila. Grishok et al. (2000); Sharp (1999); Sharp & Zamore (1999).

[0152] Several principles are worth note (see Plasterk & Ketting, 2000) First, the dsRNA should be directed to an exon, although some exceptions to this rule have been shown. Second, a homology threshold (probably about 80-85% over 200 bases) is required. Most tested sequences are 500 base pairs or greater. Third, the targeted mRNA is lost after RNAi. Fourth, the effect is non-stoichometric, and thus incredibly potent. In fact, it has been estimated that only a few copies of dsRNA are required to knock down >95% of targeted gene expression in a cell. Fire et al. (1998). Recently, shorter (˜20 base pairs) synthetic duplex RNAs have been shown to efficiently perform RNAi, by using liposome transfection. Further, similar short interfering RNA (siRNA) duplexes of 19-25 base pairs have been used by transfection via recombinant DNA constructs containing a promoter for U6 small nuclear RNA (snRNA) to drive nuclear expression of a single RNA transcript. This is also known as the hairpin siRNA/suppression of endogenous RNA (SUPER) strategy and has been shown to eliminate the expression of a target gene in longterm mammalian cell cultures (Brummelkamp et al., Science 2002; 296: 550-553; Paul et al., Nature Biotechnol 2002; 20: 505-508.; Lee et al., Nature Biotechnol 2002; 19: 500-505; Miyagishi et al., Nature Biotechnol 2002; 19: 497-500).

[0153] Although the precise mechanism of RNAi is still unknown, the involvement of permanent gene modification or the disruption of transcription have been experimentally eliminated. It is now generally accepted that RNAi acts post-transcriptionally, targeting RNA transcripts for degradation. It appears that both nuclear and cytoplasmic RNA can be targeted. Bosher and Labouesse (2000).

[0154] 5. Single Chain Antibodies

[0155] Naturally-occurring antibodies (of isotype IgG) produced by B cells, consist of four polypeptide chains. Two heavy chains (composed of four immunoglobulin domains) and two light chains (made up of two immunoglobulin domains) are held together by disulphide bonds. The bulk of the antibody complex is made up of constant immunoglobulin domains. These have a conserved amino acid sequence, and exhibit low variability. Different classes of constant regions in the stem of the antibody generate different isotypes of antibody with differing properties. The recognition properties of the antibody are carried by the variable regions (VH and VL) at the ends of the arms. Each variable domain contains three hypervariable regions known as complementarity determining regions, or CDRs. The CDRs come together in the final tertiary structure to form an antigen binding pocket. The human genome contains multiple fragments encoding portions of the variable domains in regions of the immunoglobulin gene cluster known as V, D and J. During B cell development these regions undergo recombination to generate a broad diversity of antibody affinities. As these B cell populations mature in the presence of a target antigen, hypermutation of the variable region takes place, with the B cells producing the most active antibodies being selected for further expansion in a process known as affinity maturation.

[0156] A major breakthrough was the generation of monoclonal antibodies, pure populations of antibodies with the same affinity. This was achieved by fusing B cells taken from immunized animals with myeloma cells. This generates a population of immortal hybridomas, from which the required clones can be selected. Monoclonal antibodies are very important research tools, and have been used in some therapies. However, they are very expensive and difficult to produce, and if used in a therapeutic context, can elicit and immune response which will destroy the antibody. This can be reduced in part by humanizing the antibody by grafting the CDRs from the parent monoclonal into the backbone of a human IgG antibody. It may be better to deliver antibodies by gene therapy, as this would hopefully provide a constant localized supply of antibody following a single dose of vector. The problems of vector design and delivery are dealt with elsewhere, but antibodies in their native form, consisting of two different polypeptide chains which need to be generated in approximately equal amounts and assembled correctly are not good candidates for gene therapy. However, it is possible to create a single polypeptide which can retain the antigen binding properties of a monoclonal antibody.

[0157] The variable regions from the heavy and light chains (VH and VL) are both approximately 110 amino acidg long. They can be linked by a 15 amino acid linker (e.g., (glycine4serine)3), which has sufficient flexibility to allow the two domains to assemble a functional antigen binding pocket. Addition of various signal sequences allows the scFv to be targeted to different organelles within the cell, or to be secreted. Addition of the light chain constant region (Ck) allows dimerization via disulphide bonds, giving increased stability and avidity. However, there is evidence that scFvs spontaneously multimerize, with the extent of aggregation (presumably via exposed hydrophobic surfaces) being dependent on the length of the glycine-serine linker.

[0158] The variable regions for constructing the scFv are obtained as follows. Using a monoclonal antibody against the target of interest, it is a simple procedure to use RT-PCR to clone out the variable regions from mRNA extracted from the parent hybridoma. Degenerate primers targeted to the relatively invariant framework regions can be used. Expression constructs are available with convenient cloning sites for the insertion of the cloned variable regions.

[0159] 6. Vectors

[0160] In accordance with the present invention, both stimulatory and inhibitory genes may be provided to cells of an MS patient and expressed therein. Stimulatory genes are generally simply copies of the gene of interest, although in some cases they may be genes, the expression of which direct the expression of the gene of interest. Inhibitory genes, discussed above, may include antisense or single-chain antibody genes.

[0161] The term “vector” is used to refer to a carrier nucleic acid molecule into which a nucleic acid sequence can be inserted f6r introduction into a cell where it can be replicated. A nucleic acid sequence can be “exogenous,” which means that it is foreign to the cell into which the vector is being introduced or that the sequence is homologous to a sequence in the cell but in a position within the host cell nucleic acid in which the sequence is ordinarily not found. Vectors include plasmids, cosmids, viruses (bacteriophage, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs). One of skill in the art would be well equipped to construct a vector through standard recombinant techniques (see, for example, Maniatis et al., 1989 and Ausubel et al., 1994, both incorporated herein by reference).

[0162] The term “expression vector” refers to any type of genetic construct comprising a nucleic acid coding for a RNA capable of being transcribed. In some cases, RNA molecules are then translated into a protein, polypeptide, or peptide. In other cases, these sequences are not translated, for example, in the production of antisense molecules or ribozymes. Expression vectors can contain a variety of “control sequences,” which refer to nucleic acid sequences necessary for the transcription and possibly translation of an operably linked coding sequence in a particular host cell. In addition to control sequences that govern transcription and translation, vectors and expression vectors may contain nucleic acid sequences that serve other functions as well and are described infra.

[0163] a. Promoters and Enhancers

[0164] A “promoter” is a control sequence that is a region of a nucleic acid sequence at which initiation and rate of transcription are controlled. It may contain genetic elements at which regulatory proteins and molecules may bind, such as RNA polymerase and other transcription factors, to initiate the specific transcription a nucleic acid sequence. The phrases “operatively positioned,” “operatively linked,” “under control,” and “under transcriptional control” mean that a promoter is in a correct functional location and/or orientation in relation to a nucleic acid sequence to control transcriptional initiation and/or expression of that sequence.

[0165] A promoter generally comprises a sequence that functions to position the start site for RNA synthesis. The best known example of this is the TATA box, but in some promoters lacking a TATA box, such as, for example, the promoter for the mammalian terminal deoxynucleotidyl transferase gene and the promoter for the SV40 late genes, a discrete element overlying the start site itself helps to fix the place of initiation. Additional promoter elements regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. To bring a coding sequence “under the control of” a promoter, one positions the 5′ end of the transcription initiation site of the transcriptional reading frame “downstream” of (i.e., 3′ of) the chosen promoter. The “upstream” promoter stimulates transcription of the DNA and promotes expression of the encoded RNA.

[0166] The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the tk promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription. A promoter may or may not be used in conjunction with an “enhancer,” which refers to a cis-acting regulatory sequence involved in the transcriptional activation of a nucleic acid sequence.

[0167] A promoter may be one naturally associated with a nucleic acid sequence, as may be obtained by isolating the 5′ non-coding sequences located upstream of the coding segment and/or exon. Such a promoter can be referred to as “endogenous.” Similarly, an enhancer may be one naturally associated with a nucleic acid sequence, located either downstream or upstream of that sequence. Alternatively, certain advantages will be gained by positioning the coding nucleic acid segment under the control of a recombinant or heterologous promoter, which refers to a promoter that is not normally associated with a nucleic acid sequence in its natural environment. A recombinant or heterologous enhancer refers also to an enhancer not normally associated with a nucleic acid sequence in its natural environment. Such promoters or enhancers may include promoters or enhancers of other genes, and promoters or enhancers isolated from any other virus, or prokaryotic or eukaryotic cell, and promoters or enhancers not “naturally occurring,” i.e., containing different elements of different transcriptional regulatory regions, and/or mutations that alter expression. For example, promoters that are most commonly used in recombinant DNA construction include the β-lactamase (penicillinase), lactose and tryptophan (trp) promoter systems. In addition to producing nucleic acid sequences of promoters and enhancers synthetically, sequences may be produced using recombinant cloning and/or nucleic acid amplification technology, including PCR™, in connection with the compositions disclosed herein (see U.S. Pat. Nos. 4,683,202 and 5,928,906, each incorporated herein by reference). Furthermore, it is contemplated the control sequences that direct transcription and/or expression of sequences within non-nuclear organelles such as mitochondria, chloroplasts, and the like, can be employed as well.

[0168] Naturally, it will be important to employ a promoter and/or enhancer that effectively directs the expression of the DNA segment in the organelle, cell type, tissue, organ, or organism chosen for expression. Those of skill in the art of molecular biology generally know the use of promoters, enhancers, and cell type combinations for protein expression, (see, for example Sambrook et al. 1989, incorporated herein by reference). The promoters employed may be constitutive, tissue-specific, inducible, and/or useful under the appropriate conditions to direct high level expression of the introduced DNA segment, such as is advantageous in the large-scale production of recombinant proteins and/or peptides. The promoter may be heterologous or endogenous. Additionally any promoter/enhancer combination (as per, for example, the Eukaryotic Promoter Data Base EPDB, www.epd.isb-sib.ch/) could also be used to drive expression. Use of a T3, T7 or SP6 cytoplasmic expression system is another possible embodiment. Eukaryotic cells can support cytoplasmic transcription from certain bacterial promoters if the appropriate bacterial polymerase is provided, either as part of the delivery complex or as an additional genetic expression construct.

[0169] Table 18 lists non-limiting examples of elements/promoters that may be employed, in the context of the present invention, to regulate the expression of a RNA. Table 19 provides non-limiting examples of inducible elements, which are regions of a nucleic acid sequence that can be activated in response to a specific stimulus.

TABLE 18
Promoter and/or Enhancer
Promoter/Enhancer              References
Immunoglobulin Heavy Chain     Banerji et al., 1983; Gilles et al., 1983; Grosschedl et al.,
                               1985; Atchinson et al., 1986, 1987; Imler et al., 1987;
                               Weinberger et al., 1984; Kiledjian et al., 1988; Porton et
                               al.; 1990
Immunoglobulin Light Chain     Queen et al., 1983; Picard et al., 1984
T-Cell Receptor                Luria et al., 1987; Winoto et al., 1989; Redondo et al.;
                               1990
HLA DQ a and/or DQ β           Sullivan et al., 1987
β-Interferon                   Goodbourn et al., 1986; Fujita et al., 1987; Goodbourn et
                               al., 1988
Interleukin-2                  Greene et al., 1989
lnterleukin-2 Receptor         Greene et al., 1989; Lin et al., 1990
MHC Class II 5                 Koch et al., 1989
MHC Class II HLA-Dra           Sherman et al., 1989
β-Actin                        Kawamoto et al., 1988; Ng et al.; 1989
Muscle Creatine Kinase         Jaynes et al., 1988; Horlick et al., 1989; Johnson et al.,
(MCK)                          1989
Prealbumin (Transthyretin)     Costa et al., 1988
Elastase I                     Ornitz et al., 1987
Metallothionein (MTII)         Karin et al., 1987; Culotta et al., 1989
Collagenase                    Pinkert et al., 1987; Angel et al., 1987
Albumin                        Pinkert et al., 1987; Tronche et al., 1989, 1990
α-Fetoprotein                  Godbout et al., 1988; Campere et al., 1989
γ-Globin                       Bodine et al., 1987; Perez-Stable et al., 1990
β-Globin                       Trudel et al., 1987
c-fos                          Cohen et al., 1987
c-HA-ras                       Triesman, 1986; Deschamps et al., 1985
Insulin                        Edlund et al., 1985
Neural Cell Adhesion Molecule  Hirsch et al., 1990
(NCAM)
α1-Antitrypsin                 Latimer et al., 1990
H2B (TH2B) Histone             Hwang et al., 1990
Mouse and/or Type I Collagen   Ripe et al., 1989
Glucose-Regulaled Proteins     Chang et al., 1989
(GRP94 and GRP78)
Rat Growth Hormone             Larsen et al., 1986
Human Serum Amyloid A (SAA)    Edbrooke et al., 1989
Troponin I (TN I)              Yutzey et al., 1989
Platelet-Derived Growth Factor Pech et al., 1989
(PDGF)
Duchenne Muscular Dystrophy    Klamut et al., 1990
SV40                           Banerji et al., 1981; Moreau et al., 1981; Sleigh et al.,
                               1985; Firak et al., 1986; Herr et al., 1986; Imbra et al.,
                               1986; Kadesch et al., 1986; Wang et al., 1986; Ondek et
                               al., 1987; Kuhl et al., 1987; Schaffner et al., 1988
Polyoma                        Swartzendruber et al., 1975; Vasseur et al., 1980; Katinka
                               et al., 1980, 1981; Tyndell et al., 1981; Dandolo et al.,
                               1983; de Villiers et al., 1984; Hen et al., 1986; Satake et
                               al., 1988; Campbell and/or Villarreal, 1988
Retroviruses                   Kriegler et al., 1982, 1983; Levinson et al., 1982; Kriegler
                               et al., 1983, 1984a, b, 1988; Bosze et al., 1986; Miksicek
                               et al., 1986; Celander et al., 1987; Thiesen et al., 1988;
                               Celander et al., 1988; Choi et al., 1988; Reisman et al.,
                               1989
Papilloma Virus                Campo et al., 1983; Lusky et al., 1983; Spandidos and/or
                               Wilkie, 1983; Spalholz et al., 1985; Lusky et al., 1986;
                               Cripe et al., 1987; Gloss et al., 1987; Hirochika et al.,
                               1987; Stephens et al., 1987
Hepatitis B Virus              Bulla et al., 1986; Jameel et al., 1986; Shaul et al., 1987;
                               Spandau et al., 1988; Vannice et al., 1988
Human Immunodeficiency Virus   Muesing et al., 1987; Hauber et al., 1988; Jakobovits et
                               al., 1988; Feng et al., 1988; Takebe et al., 1988; Rosen et
                               al., 1988; Berkhout et al., 1989; Laspia et al., 1989; Sharp
                               et al., 1989; Braddock et al., 1989
Cytomegalovirus (CMV)          Weber et al., 1984; Boshart et al., 1985; Foecking et al.,
                               1986
Gibbon Ape Leukemia Virus      Holbrook et al., 1987; Quinn et al., 1989

[0170]

TABLE 19
Inducible Elements
Element	Inducer	References
MT II	Phorbol Ester (TFA)	Palmiter et al., 1982;
	Heavy metals	Haslinger et al., 1985;
		Searle et al., 1985; Stuart et
		al., 1985; Imagawa et al.,
		1987, Karin et al., 1987;
		Angel et al., 1987b;
		McNeall et al., 1989
MMTV (mouse	Glucocorticoids	Huang et al., 1981;
mammary tumor		Lee et al., 1981; Majors et
virus)		al., 1983; Chandler et al.,
		1983; Lee et al., 1984;
		Ponta et al., 1985; Sakai et
		al., 1988
β-Interferon	Poly(rI)x	Tavrnier et al., 1983
	Poly(rc)
Adenovirus 5 E2	ElA	Imperiale et al., 1984
Collagenase	Phorbol Ester (TPA)	Angel et al., 1987a
Stromelysin	Phorbol Ester (TPA)	Angel et al., 1987b
SV40	Phorbol Ester (TPA)	Angel et al., 1987b
Murine MX Gene	Interferon, Newcastle	Hug et al., 1988
	Disease Virus
GRP78 Gene	A23187	Resendez et al., 1988
α-2-Macroglobulin	IL-6	Kunz et al., 1989
Vimentin	Serum	Rittling et al., 1989
MHC Class I Gene	Interferon	Blanar et al., 1989
H-2κb
HSP70	ElA, SV40 Large T	Taylor et al., 1989, 1990a,
	Antigen	1990b
Proliferin	Phorbol Ester-TPA	Mordacq et al., 1989
Tumor Necrosis	PMA	Hensel et al., 1989
Factor α
Thyroid Stimulating	Thyroid Hormone	Chatterjee et al., 1989
Hormone α Gene

[0171] The identity of tissue-specific promoters or elements, as well as assays to characterize their activity, is well known to those of skill in the art. Non-limiting examples of such regions include the human LIMK2 gene (Nomoto et al., 1999), the somatostatin receptor 2 gene (Kraus et al., 1998), murine epididymal retinoic acid-binding gene (Lareyre et al., 1999), human CD4 (Zhao-Emonet et al., 1998), mouse α2 (XI) collagen (Tsumaki et al, 1998), D1A dopamine receptor gene (Lee et al., 1997), insulin-like growth factor II (Wu et al., 1997), and human platelet endothelial cell adhesion molecule-1 (Almendro et al., 1996).

[0172] b. Initiation Signals and Internal Ribosome Binding Sites

[0173] A specific initiation signal also may be required for efficient translation of coding sequences. These signals include the ATG initiation codon or adjacent sequences. Exogenous translational control signals, including the ATG initiation codon, may need to be provided. One of ordinary skill in the art would readily be capable of determining this and providing the necessary signals. It is well known that the initiation codon must be “in-frame” with the reading frame of the desired coding sequence to ensure translation of the entire insert. The exogenous translational control signals and initiation codons can be either natural or synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements.

[0174] In certain embodiments of the invention, the use of internal ribosome entry sites (IRES) elements are used to create multigene, or polycistronic, messages. IRES elements are able to bypass the ribosome scanning model of 5′-methylated Cap dependent translation and begin translation at internal sites (Pelletier and Sonenberg, 1988). IRES elements from two members of the picornavirus family (polio and encephalomyocarditis) have been described (Pelletier and Sonenberg, 1988), as well an IRES from a mammalian message (Macejak and Sarnow, 1991). IRES elements can be linked to heterologous open reading frames. Multiple open reading frames can be transcribed together, each separated by an IRES, creating polycistronic messages. By virtue of the IRES element, each open reading frame is accessible to ribosomes for efficient translation. Multiple genes can be efficiently expressed using a single promoter/enhancer to transcribe a single message (see U.S. Pat. Nos. 5,925,565 and 5,935,819, each herein incorporated by reference).

[0175] c. Multiple Cloning Sites

[0176] Vectors can include a multiple cloning site (MCS), which is a nucleic acid region that contains multiple restriction enzyme sites, any of which can be used in conjunction with standard recombinant technology to digest the vector (see, for example, Carbonelli et al., 1999, Levenson et al., 1998, and Cocea, 1997, incorporated herein by reference.) “Restriction enzyme digestion” refers to catalytic cleavage of a nucleic acid molecule with an enzyme that functions only at specific locations in a nucleic acid molecule. Many of these restriction enzymes are commercially available. Use of such enzymes is widely understood by those of skill in the art. Frequently, a vector is linearized or fragmented using a restriction enzyme that cuts within the MCS to enable exogenous sequences to be ligated to the vector. “Ligation” refers to the process of forming phosphodiester bonds between two nucleic acid fragments, which may or may not be contiguous with each other. Techniques involving restriction enzymes and ligation reactions are well known to those of skill in the art of recombinant technology.

[0177] d. Splicing Sites

[0178] Most transcribed eukaryotic RNA molecules will undergo RNA splicing to remove introns from the primary transcripts. Vectors containing genomic eukaryotic sequences may require donor and/or acceptor splicing sites to ensure proper processing of the transcript for protein expression (see, for example, Chandler et al., 1997, herein incorporated by reference).

[0179] e. Termination Signals

[0180] The vectors or constructs of the present invention will generally comprise at least one termination signal. A “termination signal” or “terminator” is comprised of the DNA sequences involved in specific termination of an RNA transcript by an RNA polymerase. Thus, in certain embodiments a termination signal that ends the production of an RNA transcript is contemplated. A terminator may be necessary in vivo to achieve desirable message levels.

[0181] In eukaryotic systems, the terminator region may also comprise specific DNA sequences that permit site-specific cleavage of the new transcript so as to expose a polyadenylation site. This signals a specialized endogenous polymerase to add a stretch of about 200 A residues (polyA) to the 3′ end of the transcript. RNA molecules modified with this polyA tail appear to more stable and are translated more efficiently. Thus, in other embodiments involving eukaryotes, it is preferred that that terminator comprises a signal for the cleavage of the RNA, and it is more preferred that the terminator signal promotes polyadenylation of the message. The terminator and/or polyadenylation site elements can serve to enhance message levels and to minimize read through from the cassette into other sequences.

[0182] Terminators contemplated for use in the invention include any known terminator of transcription described herein or known to one of ordinary skill in the art, including but not limited to, for example, the termination sequences of genes, such as for example the bovine growth hormone terminator or viral termination sequences, such as for example the SV40 terminator. In certain embodiments, the termination signal may be a lack of transcribable or translatable sequence, such as due to a sequence truncation.

[0183] f. Polyadenylation Signals

[0184] In expression, particularly eukaryotic expression, one will typically include a polyadenylation signal to effect proper polyadenylation of the transcript. The nature of the polyadenylation signal is not believed to be crucial to the successful practice of the invention, and any such sequence may be employed. Preferred embodiments include the SV40 polyadenylation signal or the bovine growth hormone polyadenylation signal, convenient and known to function well in various target cells. Polyadenylation may increase the stability of the transcript or may facilitate cytoplasmic transport.

[0185] g. Origins of Replication

[0186] In order to propagate a vector in a host cell, it may contain one or more origins of replication sites (often termed “ori”), which is a specific nucleic acid sequence at which replication is initiated. Alternatively an autonomously replicating sequence (ARS) can be employed if the host cell is yeast.

[0187] h. Selectable and Screenable Markers

[0188] In certain embodiments of the invention, cells containing a nucleic acid construct of the present invention may be identified in vitro or in vivo by including a marker in the expression vector. Such markers would confer an identifiable change to the cell permitting easy identification of cells containing the expression vector. Generally, a selectable marker is one that confers a property that allows for selection. A positive selectable marker is one in which the presence of the marker allows for its selection, while a negative selectable marker is one in which its presence prevents its selection. An example of a positive selectable marker is a drug resistance marker.

[0189] Usually the inclusion of a drug selection marker aids in the cloning and identification of transformants, for example, genes that confer resistance to neomycin, puromycin, hygromycin, DHFR, GPT, zeocin and histidinol are useful selectable markers. In addition to markers conferring a phenotype that allows for the discrimination of transformants based on the implementation of conditions, other types of markers including screenable markers such as GFP, whose basis is colorimetric analysis, are also contemplated. Alternatively, screenable enzymes such as herpes simplex virus thymidine kinase (tk) or chloramphenicol acetyltransferase (CAT) may be utilized. One of skill in the art would also know how to employ immunologic markers, possibly in conjunction with FACS analysis. The marker used is not believed to be important, so long as it is capable of being expressed simultaneously with the nucleic acid encoding a gene product. Further examples of selectable and screenable markers are well known to one of skill in the art.

[0190] i. Plasmid Vectors

[0191] In certain embodiments, a plasmid vector is contemplated for use to transform a host cell. In general, plasmid vectors containing replicon and control sequences which are derived from species compatible with the host cell are used in connection with these hosts. The vector ordinarily carries a replication site, as well as marking sequences which are capable of providing phenotypic selection in transformed cells. In a non-limiting example, E. coli is often transformed using derivatives of pBR322, a plasmid derived from an E. coli species. pBR322 contains genes for ampicillin and tetracycline resistance and thus provides easy means for identifying transformed cells. The pBR plasmid, or other microbial plasmid or phage must also contain, or be modified to contain, for example, promoters which can be used by the microbial organism for expression of its own proteins.

[0192] In addition, phage vectors containing replicon and control sequences that are compatible with the host microorganism can be used as transforming vectors in connection with these hosts. For example, the phage lambda GEM™ 11 may be utilized in making a recombinant phage vector which can be used to transform host cells, such as, for example, E. coli LE392.

[0193] Further useful plasmid vectors include pIN vectors (Inouye et al., 1985); and pGEX vectors, for use in generating glutathione S-transferase (GST) soluble fusion proteins for later purification and separation or cleavage. Other suitable fusion proteins are those with β-galactosidase, ubiquitin, and the like.

[0194] Bacterial host cells, for example, E. coli, comprising the expression vector, are grown in any of a number of suitable media, for example, LB. The expression of the recombinant protein in certain vectors may be induced, as would be understood by those of skill in the art, by contacting a host cell with an agent specific for certain promoters, e.g., by adding IPTG to the media or by switching incubation to a higher temperature. After culturing the bacteria for a further period, generally of between 2 and 24 h, the cells are collected by centrifugation and washed to remove residual media.

[0195] j. Viral Vectors

[0196] The ability of certain viruses to infect cells or enter cells via receptor-mediated endocytosis, and to integrate into host cell genome and express viral genes stably and efficiently have made them attractive candidates for the transfer of foreign nucleic acids into cells (e.g., mammalian cells). Non-limiting examples of virus vectors that may be used to deliver a nucleic acid of the present invention are described below.

[0197] 1. Adenoviral Vectors

[0198] A particular method for delivery of the nucleic acid involves the use of an adenovirus expression vector. Although adenovirus vectors are known to have a low capacity for integration into genomic DNA, this feature is counterbalanced by the high efficiency of gene transfer afforded by these vectors. “Adenovirus expression vector” is meant to include those constructs containing adenovirus sequences sufficient to (a) support packaging of the construct and (b) to ultimately express a tissue or cell-specific construct that has been cloned therein. Knowledge of the genetic organization or adenovirus, a 36 kb, linear, double-stranded DNA virus, allows substitution of large pieces of adenoviral DNA with foreign sequences up to 7 kb (Grunhaus and Horwitz, 1992).

[0199] 2. AAV Vectors

[0200] The nucleic acid may be introduced into the cell using adenovirus assisted transfection. Increased transfection efficiencies have been reported in cell systems using adenovirus coupled systems (Kelleher and Vos, 1994; Cotten et al, 1992; Curiel, 1994). Adeno-associated virus (AAV) is an attractive vector system as it has a high frequency of integration and it can infect non-dividing cells, thus making it useful for delivery of genes into mammalian cells, for example, in tissue culture (Muzyczka, 1992) or in vivo. AAV has a broad host range for infectivity (Tratschin et al., 1984; Laughlin et al., 1986; Lebkowski et al., 1988; McLaughlin et al., 1988). Details concerning the generation and use of rAAV vectors are described in U.S. Pat. Nos. 5,139,941 and 4,797,368, each incorporated herein by reference.

[0201] 3. Retroviral Vectors

[0202] Retroviruses have promise as gene delivery vectors due to their ability to integrate their genes into the host genome, transferring a large amount of foreign genetic material, infecting a broad spectrum of species and cell types and of being packaged in special cell-lines (Miller, 1992).

[0203] In order to construct a retroviral vector, a nucleic acid (e.g., one encoding gene of interest) is inserted into the viral genome in the place of certain viral sequences to produce a virus that is replication-defective. In order to produce virions, a packaging cell line containing the gag, pol, and env genes but without the LTR and packaging components is constructed (Mann et al., 1983). When a recombinant plasmid containing a cDNA, together with the retroviral LTR and packaging sequences is introduced into a special cell line (e.g., by calcium phosphate precipitation for example), the packaging sequence allows the RNA transcript of the recombinant plasmid to be packaged into viral particles, which are then secreted into the culture media (Nicolas and Rubenstein, 1988; Temin, 1986; Mann et al., 1983). The media containing the recombinant retroviruses is then collected, optionally concentrated, and used for gene transfer. Retroviral vectors are able to infect a broad variety of cell types. However, integration and stable expression require the division of host cells (Paskind et al., 1975).

[0204] Lentiviruses are complex retroviruses, which, in addition to the common retroviral genes gag, pol, and env, contain other genes with regulatory or structural function. Lentiviral vectors are well known in the art (see, for example, Naldini et al., 1996; Zufferey et al., 1997; Blomer et al., 1997; U.S. Pat. Nos. 6,013,516 and 5,994,136). Some examples of lentivirus include the Human Immunodeficiency Viruses: HIV-1, HIV-2 and the Simian Immunodeficiency Virus: SIV. Lentiviral vectors have been generated by multiply attenuating the HIV virulence genes, for example, the genes env, vif vpr, vpu and nef are deleted making the vector biologically safe.

[0205] Recombinant lentiviral vectors are capable of infecting non-dividing cells and can be used for both in vivo and ex vivo gene transfer and expression of nucleic acid sequences. For example, recombinant lentivirus capable of infecting a non-dividing cell wherein a suitable host cell is transfected with two or more vectors carrying the packaging functions, namely gag, pol and env, as well as rev and tat is described in U.S. Pat. No. 5,994,136, incorporated herein by reference. One may target the recombinant virus by linkage of the envelope protein with an antibody or a particular ligand for targeting to a receptor of a particular cell-type. By inserting a sequence (including a regulatory region) of interest into the viral vector, along with another gene which encodes the ligand for a receptor on a specific target cell, for example, the vector is now target-specific.

[0206] 4. Other Viral Vectors

[0207] Other viral vectors may be employed as vaccine constructs in the present invention. Vectors derived from viruses such as vaccinia virus (Ridgeway, 1988; Baichwal and Sugden, 1986; Coupar et al., 1988), sindbis virus, cytomegalovirus and herpes simplex virus may be employed. They offer several attractive features for various mammalian cells (Friedmann, 1989; Ridgeway, 1988; Baichwal and Sugden, 1986; Coupar et al., 1988; Horwich et al., 1990).

[0208] 5. Delivery Using Modified Viruses

[0209] A nucleic acid to be delivered may be housed within an infective virus that has been engineered to express a specific binding ligand. The virus particle will thus bind specifically to the cognate receptors of the target cell and deliver the contents to the cell. A novel approach designed to allow specific targeting of retrovirus vectors was developed based on the chemical modification of a retrovirus by the chemical addition of lactose residues to the viral envelope. This modification can permit the specific infection of hepatocytes via sialoglycoprotein receptors.

[0210] Another approach to targeting of recombinant retroviruses was designed in which biotinylated antibodies against a retroviral envelope protein and against a specific cell receptor were used. The antibodies were coupled via the biotin components by using streptavidin (Roux et al., 1989). Using antibodies against major histocompatibility complex class I and class II antigens, they demonstrated the infection of a variety of human cells that bore those surface antigens with an ecotropic virus in vitro (Roux et al., 1989).

[0211] 7. Vector Delivery and Cell Transformation

[0212] Suitable methods for nucleic acid delivery for transformation of an organelle, a cell, a tissue or an organism for use with the current invention are believed to include virtually any method by which a nucleic acid (e.g., DNA) can be introduced into an organelle, a cell, a tissue or an organism, as described herein or as would be known to one of ordinary skill in the art. Such methods include, but are not limited to, direct delivery of DNA such as by ex vivo transfection (Wilson et al., 1989, Nabel and Baltimore, 1987), by injection (U.S. Pat. Nos. 5,994,624, 5,981,274, 5,945,100, 5,780,448, 5,736,524, 5,702,932, 5,656,610, 5,589,466 and 5,580,859, each incorporated herein by reference), including microinjection (Harlan and Weintraub, 1985; U.S. Pat. No. 5,789,215, incorporated herein by reference); by electroporation (U.S. Pat. No. 5,384,253, incorporated herein by reference; Tur-Kaspa et al, 1986; Potter et al., 1984); by calcium phosphate precipitation (Graham and Van Der Eb, 1973; Chen and Okayama, 1987; Rippe et al., 1990); by using DEAE-dextran followed by polyethylene glycol (Gopal, 1985); by direct sonic loading (Fechheimer et al., 1987); by liposome mediated transfection (Nicolau and Sene, 1982; Fraley et al., 1979; Nicolau et al., 1987; Wong et al., 1980; Kaneda et al., 1989; Kato et al., 1991) and receptor-mediated transfection (Wu and Wu, 1987; Wu and Wu, 1988); by microprojectile bombardment (PCT Application Nos. WO 94/09699 and 95/06128; U.S. Pat. Nos. 5,610,042; 5,322,783 5,563,055, 5,550,318, 5,538,877 and 5,538,880, and each incorporated herein by reference); by agitation with silicon carbide fibers (Kaeppler et al., 1990; U.S. Pat. Nos. 5,302,523 and 5,464,765, each incorporated herein by reference); by Agrobacterium-mediated transformation (U.S. Pat. Nos. 5,591,616 and 5,563,055, each incorporated herein by reference); by PEG-mediated transformation of protoplasts (Omirulleh et al., 1993; U.S. Pat. Nos. 4,684,611 and 4,952,500, each incorporated herein by reference); by desiccation/inhibition-mediated DNA uptake (Potrykus et al., 1985), and any combination of such methods. Through the application of techniques such as these, organelle(s), cell(s), tissue(s) or organism(s) may be stably or transiently transformed.

[0213] a. Injection

[0214] In certain embodiments, a nucleic acid may be delivered to an organelle, a cell, a tissue or an organism via one or more injections (i.e., a needle injection), such as, for example, subcutaneously, intradermally, intramuscularly, intervenously, intraperitoneally, etc. Methods of injection of vaccines are well known to those of ordinary skill in the art (e.g., injection of a composition comprising a saline solution). Further embodiments of the present invention include the introduction of a nucleic acid by direct microinjection. Direct microinjection has been used to introduce nucleic acid constructs into Xenopus oocytes (Harland and Weintraub, 1985).

[0215] b. Electroporation

[0216] In certain embodiments of the present invention, a nucleic acid is introduced into an organelle, a cell, a tissue or an organism via electroporation. Electroporation involves the exposure of a suspension of cells and DNA to a high-voltage electric discharge. In some variants of this method, certain cell wall-degrading enzymes, such as pectin-degrading enzymes, are employed to render the target recipient cells more susceptible to transformation by electroporation than untreated cells (U.S. Pat. No. 5,384,253, incorporated herein by reference). Alternatively, recipient cells can be made more susceptible to transformation by mechanical wounding.

[0217] Transfection of eukaryotic cells using electroporation has been quite successful. Mouse pre-B lymphocytes have been transfected with human kappa-immunoglobulin genes (Potter et al., 1984), and rat hepatocytes have been transfected with the chloramphenicol acetyltransferase gene (Tur-Kaspa et al., 1986) in this manner.

[0218] c. Calcium Phosphate

[0219] In other embodiments of the present invention, a nucleic acid may be introduced to the cells using calcium phosphate precipitation in an ex vivo context. Human KB cells have been transfected with adenovirus 5 DNA (Graham and Van Der Eb, 1973) using this technique. Also in this manner, mouse L(A9), mouse C127, CHO, CV-1, BHK, NIH3T3 and HeLa cells were transfected with a neomycin marker gene (Chen and Okayama, 1987), and rat hepatocytes were transfected with a variety of marker genes (Rippe et al., 1990).

[0220] d. DEAE-Dextran

[0221] In another embodiment, a nucleic acid is delivered into a cell using DEAE-dextran followed by polyethylene glycol. In this manner, reporter plasmids were introduced into mouse myeloma and erythroleukemia cells (Gopal, 1985).

[0222] e. Sonication Loading

[0223] Additional embodiments of the present invention include the introduction of a nucleic acid by direct sonic loading. LTK-fibroblasts have been transfected with the thymidine kinase gene by sonication loading (Fechheimer et al., 1987).

[0224] f. Liposome-Mediated Transfection

[0225] In a further embodiment of the invention, a nucleic acid may be entrapped in a lipid complex such as, for example, a liposome. Liposomes are vesicular structures characterized by a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh and Bachhawat, 1991). Also contemplated is an nucleic acid complexed with Lipofectamine (Gibco BRL) or Superfect (Qiagen).

[0226] Liposome-mediated nucleic acid delivery and expression of foreign DNA in vitro has been very successful (Nicolau and Sene, 1982; Fraley et al., 1979; Nicolau et al., 1987). The feasibility of liposome-mediated delivery and expression of foreign DNA in cultured chick embryo, HeLa and hepatoma cells has also been demonstrated (Wong et al., 1980).

[0227] In certain embodiments of the invention, a liposome may be complexed with a hemagglutinating virus (HVJ). This has been shown to facilitate fusion with the cell membrane and promote cell entry of liposome-encapsulated DNA (Kaneda et al., 1989). In other embodiments, a liposome may be complexed or employed in conjunction with nuclear non-histone chromosomal proteins (HMG-1) (Kato et al., 1991). In yet further embodiments, a liposome may be complexed or employed in conjunction with both HVJ and HMG-1. In other embodiments, a delivery vehicle may comprise a ligand and a liposome.

[0228] g. Receptor Mediated Transfection

[0229] Still further, a nucleic acid may be delivered to a target cell via receptor-mediated delivery vehicles. These take advantage of the selective uptake of macromolecules by receptor-mediated endocytosis that will be occurring in a target cell. In view of the cell type-specific distribution of various receptors, this delivery method adds another degree of specificity to the present invention.

[0230] Certain receptor-mediated gene targeting vehicles comprise a cell receptor-specific ligand and a nucleic acid-binding agent. Others comprise a cell receptor-specific ligand to which the nucleic acid to be delivered has been operatively attached. Several ligands have been used for receptor-mediated gene transfer (Wu and Wu, 1987; Wagner et al., 1990; Perales et al., 1994; Myers, EPO 0273085), which establishes the operability of the technique. Specific delivery in the context of another mammalian cell type has been described (Wu and Wu, 1993; incorporated herein by reference). In certain aspects of the present invention, a ligand will be chosen to correspond to a receptor specifically expressed on the target cell population.

[0231] In other embodiments, a nucleic acid delivery vehicle component of a cell-specific nucleic acid targeting vehicle may comprise a specific binding ligand in combination with a liposome. The nucleic acid(s) to be delivered are housed within the liposome and the specific binding ligand is functionally incorporated into the liposome membrane. The liposome will thus specifically bind to the receptor(s) of a target cell and deliver the contents to a cell. Such systems have been shown to be functional using systems in which, for example, epidermal growth factor (EGF) is used in the receptor-mediated delivery of a nucleic acid to cells that exhibit upregulation of the EGF receptor.

[0232] In still further embodiments, the nucleic acid delivery vehicle component of a targeted delivery vehicle may be a liposome itself, which will preferably comprise one or more lipids or glycoproteins that direct cell-specific binding. For example, lactosyl-ceramide, a galactose-terminal asialganglioside, have been incorporated into liposomes and observed an increase in the uptake of the insulin gene by hepatocytes (Nicolau et al., 1987). It is contemplated that the tissue-specific transforming constructs of the present invention can be specifically delivered into a target cell in a similar manner.

[0233] h. Microprojectile Bombardment

[0234] Microprojectile bombardment techniques can be used to introduce a nucleic acid ex vivo into at least one, organelle, cell, or tissue (U.S. Pat. Nos. 5,550,318, 5,538,880, 5,610,042, and PCT Application WO 94/09699; each of which is incorporated herein by reference). This method depends on the ability to accelerate DNA-coated microprojectiles to a high velocity allowing them to pierce cell membranes and enter cells without killing them (Klein et al, 1987). There are a wide variety of microprojectile bombardment techniques known in the art, many of which are applicable to the invention.

[0235] In this microprojectile bombardment, one or more particles may be coated with at least one nucleic acid and delivered into cells by a propelling force. Several devices for accelerating small particles have been developed. One such device relies on a high voltage discharge to generate an electrical current, which in turn provides the motive force (Yang et al., 1990). The microprojectiles used have consisted of biologically inert substances such as tungsten or gold particles or beads. Exemplary particles include those comprised of tungsten, platinum, and preferably, gold. It is contemplated that in some instances DNA precipitation onto metal particles would not be necessary for DNA delivery to a recipient cell using microprojectile bombardment. However, it is contemplated that particles may contain DNA rather than be coated with DNA. DNA-coated particles may increase the level of DNA delivery via particle bombardment but are not, in and of themselves, necessary.

[0236] For the bombardment, cells in suspension are concentrated on filters or solid culture medium. Alternatively, immature embryos or other target cells may be arranged on solid culture medium. The cells to be bombarded are positioned at an appropriate distance below the macroprojectile stopping plate.

[0237] An illustrative embodiment of a method for delivering DNA into a cell (e.g., a plant cell) by acceleration is the Biolistics Particle Delivery System, which can be used to propel particles coated with DNA or cells through a screen, such as a stainless steel or Nytex screen, onto a filter surface covered with cells, such as for example, a monocot plant cells cultured in suspension. The screen disperses the particles so that they are not delivered to the recipient cells in large aggregates. It is believed that a screen intervening between the projectile apparatus and the cells to be bombarded reduces the size of projectiles aggregate and may contribute to a higher frequency of transformation by reducing the damage inflicted on the recipient cells by projectiles that are too large.

[0238] VII. Pharmaceutical Formulations and Routes of Administration

[0239] Where clinical applications are contemplated, it will be necessary to prepare pharmaceutical compositions in a form appropriate for the intended application. Generally, this will entail preparing compositions that are essentially free of pyrogens, as well as other impurities that could be harmful to humans or animals.

[0240] The phrase “pharmaceutically or pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplementary active ingredients also can be incorporated into the compositions.

[0241] Administration of these compositions according to the present invention will be via any common route so long as the target tissue is available via that route. This includes intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions, described supra.

[0242] The active compounds also may be administered parenterally or intraperitoneally. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0243] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy administration by a syringe is possible. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial an antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0244] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0245] For oral administration the polypeptides of the present invention may be incorporated with excipients that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.

[0246] As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0247] The compositions of the present invention may be formulated in a neutral or salt form. Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

VIII. EXAMPLES

[0248] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

Materials and Methods

[0249] RNA isolation and hybridization of biotin-labeled cRNA to HuFL6800 GeneChips. Peripheral blood obtained from MS patients, ALS patients and healthy donors was subjected to Ficoll-paque gradient centrifugation for isolation of whole mononuclear cells (also known as peripheral blood mononuclear cells or PBMCs). RNA was then isolated using the Trizol (Gibco BRL) method. The inventors used protocols for cRNA preparation and biotin labeling for use with the Affymetrix HuFL6800 microarrays that have been published (Warrington et al., 2000). Briefly, the method is described below:

[0250] The HuFL6800 microarrays contain 7,070 distinct probe sets, representing approximately 6,800 human genes. Briefly, using 7-10 μg of total RNA, double stranded cDNA was synthesized using the Superscript Choice System (Life Technologies) with the following modifications. In the first strand synthesis, the reverse transcription reaction contained a T7(dT)24 primer plus 0.1 M DTT and 10 mM dNTP mix. For second strand synthesis, E. coli DNA ligase (10 U/μl) and T4 DNA Polymerase I (10 U/μl), 10 mM dNTP mix and RNase H (2 U/μl) were used. Phenol-chloroform extraction was followed by in vitro transcription (IVT) (Enzo Bioarray™ High Yield™ RNA transcript labeling kit, distributed by Affimetrix, Inc.) with biotin labeling. IVT was performed with (1:3) biotinylated: unlabeled CTP and UTP. The T7 enzyme mix and T7 transcription buffer were added to the ds cDNA and NTP labeling mix (ATP, CTP, UTP, GTP, Bio-11-CTP and Bio-16-UTP). The NTP labeling mix was incubated for 5 hr at 37° C., and cleaned using RNeasy columns (Qiagen). 13-20 μg of fluorescently-labeled and chemically-fragmented cRNA were used for array hybridization. Fragmented cRNA and herring sperm DNA were added to the hybridization buffer containing 1.0 M NaCl, 10 mM Tris-HCL pH 7.6, and 0.01% Triton X-100.

[0251] The hybridization mixture was heated to 99° C. for 5 min., spun, and incubated at 45° C. for 5 min, and injected into the probe array cartridge. Hybridizations were carried out at 45° C. for 16 hours with mixing at 60 rpm. Following hybridization, solutions were removed, and arrays were rinsed and incubated with 0.1×ST-T (100 mM NaCl, 10 mM Tris-HCL pH 8.0, and 0.01% Triton X-100) at 50° C. for 20 min. Hybridized arrays were stained with 5.0 μg/ml streptavidin-phycoerythrin (Molecular Probes) and 2.0 mg/ml acetylated BSA (Sigma) in 1×ST-T at 40° C. for 15 min. The streptavidin-phycoerythrin step was repeated after an intermediate amplification step in which anti-streptavidin rabbit IgG antibodies and secondary biotinylated goat anti-rabbit antibodies are added to the samples. Following washes, probe arrays were scanned twice at 6 μm resolution using the GeneChip system confocal scanner.

[0252] Analysis was performed using Affymetrix Microarray Suite software, which assesses presence or absence of transcripts for each probe set, taking into account metrics such as background, noise, and comparison of intensities between Perfect Match (PM) and their control Mismatch (MM) probe cells. The average intensity of each microarray was scaled to a target intensity of 1500. Prior to statistical analysis, all average difference intensity values of less than 20 and all negative values were assigned a set value of 20. Results from each sample were grouped into a defined class (i.e., MS, MS on Avonex, ALS, and healthy donors).

[0253] Selection of Discriminatory Genes. Several statistical measures have been introduced to identify discriminatory genes for two conditions (e.g., cancerous and normal tissues). Parametric tests such as P-value (Golub et al., 1999) and t-test (Thomas et al. 2001) are based on differences of group means, while non-parametric tests such as Wilcoxon rank sum (MannWhitney) test are based on differences of rank sums in groups (Thomas et al., 2001). A couple of measures such as Wilks' lambda were also proposed for the identification of discriminatory genes in multi-classes (Dudoit et al., 2001). All these measures have their own advantages and disadvantages and no method is thus unanimously optimal for all kinds of data. Parametric tests may perform poorly due to violation of their underlying assumptions, such as normality and equal variance in the various groups. A non-parametric test does not rely on these assumptions and works well with a small sample size, but the results may be more critically sensitive on the nature of the samples used for the training of the classifier than those in parametric tests. For these reasons, many methods normally yield various levels of false positive discriminatory genes, depending on the degree of how the method used violates the underlying assumptions for a given data set and is sensitive to the sample size.

[0254] A few methods such as Significance Analysis of Microarrays (SAM) (Storey et al., 2001; Tusher et al., 2001) have been introduced to reduce false positive error rate in identifying discriminatory genes. These methods do not directly estimate the probability of false positive errors to calculate a false positive error rate. However, they introduce both a typical measure (e.g., simple t-test) to produce a large set of discriminatory genes including many false positives, and a more stringent measure (e.g., permutation based SAM) to produce a smaller set of genes only with high discriminatory characteristics. A false discovery rate is then indirectly estimated based on the reduction of the size of the latter set of discriminatory genes, with respect to the former set. Here, the inventors introduce a novel method for discriminatory gene selection that directly estimates the probability of false positive error for a given false negative error, thus more precisely eliminating false positives. This method involves a standard statistical test (e.g., t-test) on the basis of the distribution of the null hypothesis (Ho: group means are same), but the unique feature in this method is to include additionally the distribution of the alternative hypothesis (H1: group means are not same). Normal t-test involves the hypothesis testing with mean difference scaled by a pooled standard deviation, based on only the distribution of H0 that the scaled mean differences follow, when the group means are same. For a given discriminatory gene whose means are distinct in classes, the scaled mean difference stays outside the H0 distribution. The normal t-test calculates the probability of observing the given scaled mean difference by chance, when H0 is true (e.g., the group means are same) (Rice, 1995; Statistics toolbox Version 2.1.1, 1997). If this probability, called significance, is less than a desired significance level (α=0.05 or 0.01), then reject the H0 and accept the H1, concluding that the gene is discriminatory. However, this significance is only calculated in the view of H0, never involving the H1 distribution. Thus, the probability that the gene is actually discriminatory (i.e., H1 is true) is not calculated before the H1 is accepted. In this light, to identify a more correct set of discriminatory genes, both distributions H0 and H1 should be simultaneously considered.

[0255] Considering the two distributions together, there are two types of errors in the standard hypothesis testing: false positive (α) and false negative (β) errors (two tailed t-test; see FIG. 1). False positive error is defined by the probability that the gene is in fact not discriminatory (i.g., H0 is true), but the test concludes that the gene is discriminatory (i.e., H1 is true), while false negative error is by the probability that the gene is in fact discriminatory, but the test concludes that the gene is not discriminatory (i.g., H0 is true) (see FIG. 1). This novel method involving these two distributions comprises two steps to determine false positive error for each gene with a given false negative error and select discriminatory genes whose estimated false positive errors are less than a certain cutoff value (α=0.05). First, the H0 and H1 distributions are first defined. While the H0 distribution in the standard t-test can be used, a non-centrality parameter (Δ) is required to define the H1 distribution, as shown in Equations 1 to 3.

H0:μ1=μ2 and H1:μ2≠μ2  (1) 1 $$ H 0 : t = ( x _ 1 - x _ 2 ) S p ⁢ 1 / n 1 + 1 / n 2 ∼ t ⁡ ( N - 2 ) ( 2 ) H 1 : t = ( x _ 1 - x _ 2 ) S p ⁢ 1 / n 1 + 1 / n 2 ∼ t ⁡ ( N - 2 ; Δ = ( x _ 1 - x _ 2 ) actual S p ⁢ 1 / n 1 + 1 / n 2 ) ( 3 )

[0256] where the bar of xi is the mean in the i-th class and Sp is the pooled standard deviation. N is the total number of samples and ni is the number of samples belonging to the i-th class. t(N-2) and t(N-2; Δ) are a central t-distribution with the degrees of freedom (d.o.f.) of N-2 and a non-central t-distribution with the same d.o.f. and the non-centrality parameter Δ. For each gene, the actual scaled mean difference is used in Equation 3 to estimate the non-centrality parameter Δ. Then, by taking the inverse of the H1 distribution, a critical t statistic value is calculated for the given false negative error (β=0.05) (see FIG. 1). Second, a false positive error for each gene can be calculated using the H0 distribution with this critical t value (see Equation 1 and FIG. 1). If this estimated false positive error is less than a certain cutoff value (α=0.05), the corresponding gene is selected as a discriminatory gene (see Discriminatory gene lists). The genes selected in this way are denoted by a set of most discriminatory genes. This procedure is schematically depicted in FIG. 1.

[0257] The standard t-test is also used to identify a set of moderately discriminatory genes and a set of less discriminatory genes. The moderately discriminatory genes are selected by a cutoff value of 0.01 for the significances of genes in the t-test, while the less discriminatory genes are by a cutoff value of 0.05.

[0258] Fisher Discriminant Analysis (FDA). Fisher Discriminant Analysis (FDA) is a linear method of dimensionality reduction from the expression space comprising all selected discriminatory genes to just a few dimensions where the separation of sample classes is maximized. FDA is similar to Principal Component Analysis (PCA) (Alter, 2000; Holter et al., 2000) in the linear reduction of data (Johnson & Wichem, 1992; Dillon & Goldstein, 1984). The major difference is that the discriminant axes of the FDA space are selected such as to maximize class separation in the reduced FDA space, instead of variability as in the case of PCA. The discriminant axes of FDA, termed as discriminant weights (V), maximizing the separation of sample classes in their projection space can be shown to be equivalent to the eigenvectors of W 1B, the ratio of between-group variance (B) to within-group variance (W), as shown in Equation 4: 2$\begin{array}{cc}{W}^{-1}\mathrm{BV}=V\Lambda \mathrm{where}B=T-W,W=\sum _{j=1}^c{\left(X_j-1{\stackrel{\_}{x}}_j^T\right)}^T\left(X_j-1{\stackrel{\_}{x}}_j^T\right),\mathrm{and}T={\left(X-1{\stackrel{\_}{x}}^T\right)}^T\left(X-1{\stackrel{\_}{x}}^T\right).& \left(4\right)\end{array}$

[0259] The eigenvalues (Λ) indicate the discrimination power for the corresponding discriminant axes. FIG. 2 shows the projection of the expression data in the 4-classes (ALS, Healthy, MS, and MS+Avonex). A classification rule can be built in the FDA space. A new sample is projected into the FDA space using the discriminant weights (V). Then, the new sample will be assigned to the predefined class whose mean is closest to the projection of the new sample (Johnson & Wichem, 1992): a new sample (x) will be allocated to class j if

∥ŷ−{overscore (y)}j∥2=({circumflex over (x)}−{overscore (x)}j)V∥2≦∥({circumflex over (x)}−{overscore (x)}k)V∥2 for all k≠j  (5)

[0260] where ŷ is a projection of the new sample into the discriminant axes (V).

[0261] All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

IX. REFERENCES

[0262] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

[0263] U.S. Pat. No. 3,817,837

[0264] U.S. Pat. No. 3,850,752

[0265] U.S. Pat. No. 3,939,350

[0266] U.S. Pat. No. 3,996,345

[0267] U.S. Pat. No. 4,275,149

[0268] U.S. Pat. No. 4,277,437

[0269] U.S. Pat. No. 4,366,241

[0270] U.S. Pat. No. 4,683,195

[0271] U.S. Pat. No. 4,683,202

[0272] U.S. Pat. No. 4,684,611

[0273] U.S. Pat. No. 4,797,368

[0274] U.S. Pat. No. 4,800,159

[0275] U.S. Pat. No. 4,883,750

[0276] U.S. Pat. No. 4,952,500

[0277] U.S. Pat. No. 5,139,941

[0278] U.S. Pat. No. 5,242,974

[0279] U.S. Pat. No. 5,279,721

[0280] U.S. Pat. No. 5,302,523

[0281] U.S. Pat. No. 5,322,783

[0282] U.S. Pat. No. 5,384,253

[0283] U.S. Pat. No. 5,384,261

[0284] U.S. Pat. No. 5,405,783

[0285] U.S. Pat. No. 5,412,087

[0286] U.S. Pat. No. 5,424,186

[0287] U.S. Pat. No. 5,429,807

[0288] U.S. Pat. No. 5,436,327

[0289] U.S. Pat. No. 5,445,934

[0290] U.S. Pat. No. 5,464,765

[0291] U.S. Pat. No. 5,472,672

[0292] U.S. Pat. No. 5,527,681

[0293] U.S. Pat. No. 5,529,756

[0294] U.S. Pat. No. 5,532,128

[0295] U.S. Pat. No. 5,538,877

[0296] U.S. Pat. No. 5,538,880

[0297] U.S. Pat. No. 5,545,531

[0298] U.S. Pat. No. 5,550,318

[0299] U.S. Pat. No. 5,554,501

[0300] U.S. Pat. No. 5,556,752

[0301] U.S. Pat. No. 5,561,071

[0302] U.S. Pat. No. 5,563,055

[0303] U.S. Pat. No. 5,571,639

[0304] U.S. Pat. No. 5,580,859

[0305] U.S. Pat. No. 5,589,466

[0306] U.S. Pat. No. 5,591,616

[0307] U.S. Pat. No. 5,593,839

[0308] U.S. Pat. No. 5,599,695

[0309] U.S. Pat. No. 5,610,042

[0310] U.S. Pat. No. 5,624,711

[0311] U.S. Pat. No. 5,656,610

[0312] U.S. Pat. No. 5,658,734

[0313] U.S. Pat. No. 5,700,637

[0314] U.S. Pat. No. 5,702,932

[0315] U.S. Pat. No. 5,736,524

[0316] U.S. Pat. No. 5,780,448

[0317] U.S. Pat. No. 5,789,215

[0318] U.S. Pat. No. 5,840,873

[0319] U.S. Pat. No. 5,843,640

[0320] U.S. Pat. No. 5,843,650

[0321] U.S. Pat. No. 5,843,651

[0322] U.S. Pat. No. 5,843,663

[0323] U.S. Pat. No. 5,846,708

[0324] U.S. Pat. No. 5,846,709

[0325] U.S. Pat. No. 5,846,717

[0326] U.S. Pat. No. 5,846,726

[0327] U.S. Pat. No. 5,846,729

[0328] U.S. Pat. No. 5,846,783

[0329] U.S. Pat. No. 5,849,481

[0330] U.S. Pat. No. 5,849,486

[0331] U.S. Pat. No. 5,849,487

[0332] U.S. Pat. No. 5,849,497

[0333] U.S. Pat. No. 5,849,546

[0334] U.S. Pat. No. 5,849,547

[0335] U.S. Pat. No. 5,851,772

[0336] U.S. Pat. No. 5,853,990

[0337] U.S. Pat. No. 5,853,992

[0338] U.S. Pat. No. 5,853,993

[0339] U.S. Pat. No. 5,856,092

[0340] U.S. Pat. No. 5,858,652

[0341] U.S. Pat. No. 5,861,244

[0342] U.S. Pat. No. 5,863,732

[0343] U.S. Pat. No. 5,863,753

[0344] U.S. Pat. No. 5,866,331

[0345] U.S. Pat. No. 5,866,336

[0346] U.S. Pat. No. 5,882,864

[0347] U.S. Pat. No. 5,900,481

[0348] U.S. Pat. No. 5,905,024

[0349] U.S. Pat. No. 5,910,407

[0350] U.S. Pat. No. 5,912,124

[0351] U.S. Pat. No. 5,912,145

[0352] U.S. Pat. No. 5,912,148

[0353] U.S. Pat. No. 5,916,776

[0354] U.S. Pat. No. 5,916,779

[0355] U.S. Pat. No. 5,919,626

[0356] U.S. Pat. No. 5,919,630

[0357] U.S. Pat. No. 5,922,574

[0358] U.S. Pat. No. 5,925,517

[0359] U.S. Pat. No. 5,925,565

[0360] U.S. Pat. No. 5,928,862

[0361] U.S. Pat. No. 5,928,869

[0362] U.S. Pat. No. 5,928,905

[0363] U.S. Pat. No. 5,928,906

[0364] U.S. Pat. No. 5,929,227

[0365] U.S. Pat. No. 5,932,413

[0366] U.S. Pat. No. 5,932,451

[0367] U.S. Pat. No. 5,935,791

[0368] U.S. Pat. No. 5,935,819

[0369] U.S. Pat. No. 5,935,825

[0370] U.S. Pat. No. 5,939,291

[0371] U.S. Pat. No. 5,942,391

[0372] U.S. Pat. No. 5,945,100

[0373] U.S. Pat. No. 5,981,274

[0374] U.S. Pat. No. 5,994,136

[0375] U.S. Pat. No. 5,994,624

[0376] U.S. Pat. No. 6,004,755

[0377] U.S. Pat. No. 6,013,516

[0378] U.S. Pat. No. 6,331,396

[0379] Abbondanzo, Ann. Diagn. Pathol., 3(5):318-327, 1999.

[0380] Allegreta et al, Science, 247(4943):718-21, 1990.

[0381] Allred et al., Arch Surg, 125(1):107-13, 1990.

[0382] Almendro et al., J Immunol., 157:5411-5421, 1996.

[0383] Alter et al., Proc. Nat'l Acad. Sci. USA, 97, 10101-10106 (2000).

[0384] Angel et al., Mol. Cell. Biol., 7:2256, 1987.

[0385] Angel et al., Cell, 49:729, 1987b.

[0386] Angel et al., Mol. Cell Biol., 7:2256, 1987a.

[0387] Atchison and Perry, Cell, 46:253, 1986.

[0388] Atchison and Perry, Cell, 48:121, 1987.

[0389] Bagasra et al., Proc. Nat'l Acad. Sci. USA, Dec. 19, 1995;92(26):12041-5

[0390] Bagasra et al., Proc. Nat'l Acad. Sci. USA, 92(26):12041-5, 1995.

[0391] Baichwal and Sugden, In: Gene Transfer, Kucherlapati (ed.), New York, Plenum Press, 117-148, 1986.

[0392] Banerji et al., Cell, 27(2 Pt 1):299-308, 1981.

[0393] Banerji et al., Cell, 33(3):729-740, 1983.

[0394] Barcellos et al., Immunogenetics, 51: 281, 2000.

[0395] Berkhout et al., Cell, 59:273-282, 1989.

[0396] Blanar et al., EMBO J, 8:1139, 1989.

[0397] Blomer et al., J. Virol., 71(9):6641-6649, 1997.

[0398] Bo et al., Ann. Neurol., 36(5):778-86, 1994.

[0399] Bodine and Ley, EMBO J., 6:2997, 1987.

[0400] Boshart et al., Cell, 41:521, 1985.

[0401] Bosher and Labouesse, Nat. Cell Biol. 2(2):E31-36, 2000.

[0402] Bosze et al., EMBO J, 5(7):1615-1623, 1986.

[0403] Braddock et al., Cell, 58:269, 1989.

[0404] Brown et al., Immunol Ser, 53:69-82, 1990.

[0405] Bulla and Siddiqui, J. Virol., 62:1437, 1986.

[0406] Campbell and Villarreal, Mol. Cell. Biol., 8: 1993, 1988.

[0407] Campere and Tilghman, Genes and Dev., 3:537, 1989.

[0408] Campo et al., Nature, 303:77, 1983.

[0409] Carbonelli et al., FEMS Microbiol Lett, 177(1):75-82, 1999.

[0410] Carlin et al., J. Neuropathol. Exp. Neurol. 59:361, 2000.

[0411] Celander and Haseltine, J. Virology, 61:269, 1987.

[0412] Celander et al., J. Virology, 62:1314, 1988.

[0413] Chamberlan et al., In: PCR Protocols, eds. Innis, Gelfand, Sninsky, White (Academic Press, NY, 272-281, 1990.

[0414] Chandler et al., Cell, 33:489, 1983.

[0415] Chang et al., Mol. Cell. Biol., 9:2153, 1989.

[0416] Chataway et al., Neurogenetics 2:91, 1999.

[0417] Chatterjee et al., Proc Nat'l Acad. Sci. U.S.A., 86:9114, 1989.

[0418] Chen and Okayama, Mol. Cell Biol., 7(8):2745-2752, 1987.

[0419] Choi et al., Cell, 53:519, 1988.

[0420] Cocea, Biotechniques, 23(5):814-816, 1997.

[0421] Cohen et al., J. Cell. Physiol., 5:75, 1987.

[0422] Costa et al., Mol. Cell. Biol., 8:81, 1988.

[0423] Cotten et al., Proc Nat'l Acad Sci USA, 89(13):6094-6098, 1992.

[0424] Coupar et al., Gene, 68:1-10, 1988.

[0425] Cripe et al., EMBO J, 6:3745, 1987.

[0426] Culotta and Hamer, Mol. Cell. Biol., 9:1376, 1989.

[0427] Curiel, Nat. Immun., 13(2-3):141-64, 1994.

[0428] Dandolo et al., J. Virology, 47:55-64, 1983.

[0429] De Groot et al., J. Neuropathol. Exp. Neurol. 56(1):10-20, 1997.

[0430] De Jager et al., Semin. Nucl. Med. 23(2):165-179, 1993.

[0431] De Villiers et al., Nature, 312(5991):242-246, 1984.

[0432] Der et al., Proc. Nat'l Acad. Sci. USA 95:15623-8, 1998.

[0433] Deschamps et al., Science, 230:1174-1177, 1985.

[0434] Dillon and Goldstein, Multivariate Analysis, Wiley, New York; 1984.

[0435] Ding et al., J. Immunol., 160(6):2560-4, 1998.

[0436] Doolittle et al., Methods Mol. Biol., 109:215-237, 1999.

[0437] Dudoit et al., UC Berkeley Statistics tech. Report, 2001.

[0438] Edbrooke et al., Mol. Cell. Biol., 9:1908, 1989.

[0439] Edlund et al., Science, 230:912-916, 1985.

[0440] Eikelenboom et al., Neurology 60, 219-223, 2003.

[0441] European Application No. 0 364 255

[0442] European Application No. 320 308

[0443] European Application No. EPO 0273085

[0444] European Application No. GB 2 202 328

[0445] European Application No. 329 822

[0446] Fechheimer et al., Proc. Nat'l Acad. Sci. USA, 84:8463-8467, 1987.

[0447] Feng and Holland, Nature, 334:6178, 1988.

[0448] Femandez-Arquero et al Neurology 53:1361, 1999.

[0449] Firak and Subramanian, Mol. Cell. Biol., 6:3667, 1986.

[0450] Fire et al., Nature, 391:806-811, 1998.

[0451] Fiten et al., J. Neuroimmunol. 95:195, 1999.

[0452] Foecking and Hofstetter, Gene, 45(1):101-105, 1986.

[0453] Fraley et al., Proc. Nat'l Acad. Sci. USA, 76:3348-3352, 1979.

[0454] Friedmann, Science, 244:1275-1281, 1989.

[0455] Frohman, In: PCR Protocols: A Guide To Methods And Applications, Academic Press, N.Y., 1990.

[0456] Fujita et al., Cell, 49:357, 1987.

[0457] Fukazawa et al., J Neurol. Sci. 166: 47, 1999.

[0458] Fukazawa et al., J Neurol. Sci. 171: 49, 1999.

[0459] Gade-Andavolu et al., Arch. Neurol. 55:513, 1998.

[0460] Ghosh and Bachhawat, In: Liver Diseases, Targeted Diagnosis and Therapy Using Specific Receptors and Ligands. Wu et al., eds., Marcel Dekker, New York, pp. 87-104, 1991.

[0461] Gilles et al., Cell, 33:717, 1983.

[0462] Giovannoni et al., J Neurol. Sci., 145(1):77-81, 1997.

[0463] Gloss et al., EMBO J., 6:3735, 1987.

[0464] Godbout et al., Mol. Cell. Biol., 8:1169, 1988.

[0465] Golub et al., Science 286, 531-537, 1999.

[0466] Goodbourn and Maniatis, Proc. Nat'l Acad. Sci. USA, 85:1447, 1988.

[0467] Goodbourn et al., Cell, 45:601, 1986.

[0468] Gopal, Mol. Cell Biol., 5:1188-1190, 1985.

[0469] Graham and Van Der Eb, Virology, 52:456-467, 1973.

[0470] Greene et al., Immunology Today, 10:272, 1989

[0471] Grishok et al., Science, 287:2494-2497, 2000.

[0472] Grosschedl and Baltimore, Cell, 41:885, 1985.

[0473] Gulbis and Galand, Hum. Pathol. 24(12):1271-1285, 1993.

[0474] Harland and Weintraub, J. Cell Biol., 101:1094-1099, 1985.

[0475] Hashimoto et al., J Neuroimmunol. 44:77, 1993.

[0476] Haslinger and Karin, Proc. Nat'l Acad. Sci. USA, 82:8572, 1985.

[0477] Hauber and Cullen, J. Virology, 62:673, 1988.

[0478] Hen et al, Nature, 321:249, 1986.

[0479] Hensel et al., Lymphokine Res., 8:347, 1989.

[0480] Herr and Clarke, Cell, 45:461, 1986.

[0481] Hintzenetal., JNI, 35:211-7, 1991.

[0482] Hirochika et al., J. Virol., 61:2599, 1987.

[0483] Hirsch et al., Mol. Cell. Biol., 10:1959, 1990.

[0484] Holbrooketal., Virology, 157:211, 1987.

[0485] Holter et al., Proc. Nat'l Acad. Sci. USA 97, 8409-8414, 2000.

[0486] Horlick and Benfield, Mol. Cell. Biol., 9:2396, 1989.

[0487] Horwich et al., Virol., 64:642-650, 1990.

[0488] Huang et al., Cell, 27:245, 1981.

[0489] Hug et al., Mol. Cell. Biol., 8:3065, 1988.

[0490] Hwang et al., Mol. Cell. Biol., 10:585, 1990.

[0491] Imagawa et al., Cell, 51:251, 1987.

[0492] Imbra and Karin, Nature, 323:555, 1986.

[0493] Imler et al., Mol. Cell. Biol, 7:2558, 1987.

[0494] Imperiale and Nevins, Mol. Cell. Biol., 4:875, 1984.

[0495] Innis et al., Proc. Nat'l Acad. Sci. USA 85(24):9436-9440, 1988.

[0496] Inouye and Inouye, Nucleic Acids Res., 13: 3101-3109, 1985.

[0497] Jacobsen et al., Nat. Genetics 26:495, 2000.

[0498] Jakobovits et al., Mol. Cell. Biol., 8:2555, 1988.

[0499] Jameel and Siddiqui, Mol. Cell. Biol., 6:710, 1986.

[0500] Jaynes et al., Mol. Cell. Biol., 8:62, 1988.

[0501] Jo et al., J. Biol. Chem., 276(19):16168-76, 2001.

[0502] Johnson and Applied Multivariate Statistical Analysis, Prentice Hall, New Jersey, 1992.

[0503] Johnson et al., Mol. Cell. Biol., 9:3393, 1989.

[0504] Johnston et al., Ann. Neurol., 50(4):434-42, 2001.

[0505] Kadesch and Berg, Mol. Cell. Biol., 6:2593, 1986.

[0506] Kaeppler et al., Plant Cell Reports 9: 415-418, 1990.

[0507] Kaneda et al., Science, 243:375-378, 1989.

[0508] Kantharia et al., Br. J. Rheumatol., 28(2):118-23, 1989.

[0509] Karin et al., Mol. Cell. Biol., 7:606, 1987.

[0510] Karin et al., Mol. Cell. Biol., 7:606, 1987.

[0511] Katinka et al., Cell, 20:393, 1980. Kato et al., J. Biol. Chem., 266:3361-3364, 1991.

[0512] Kawamoto et al., Mol. Cell. Biol., 8:267, 1988.

[0513] Kelleher and Vos, Biotechniques, 17(6):1110-7, 1994.

[0514] Ketting et al., Cell, 99:133-141, 1999.

[0515] Kiledjian et al., Mol. Cell. Biol., 8:145, 1988.

[0516] Klamut et al., Mol. Cell. Biol., 10: 193, 1990.

[0517] Klein et al., Nature, 327:70-73, 1987.

[0518] Knobeloch et al., Mol. Cell. Biol., 20(15):5363-9, 2000.

[0519] Koch et al., Mol. Cell. Biol., 9:303, 1989.

[0520] Kotze et al., Blood Cells Mol. Dis., 27(1):44-53, 2001.

[0521] Kraus et al., FEBS Lett., 428(3):165-170, 1998.

[0522] Kriegler and Botchan, In: Eukaryotic Viral Vectors, Y. Gluzman, ed., Cold Spring Harbor: Cold Spring Harbor Laboratory, NY, 1982.

[0523] Kriegler and Botchan, Mol. Cell. Biol., 3:325, 1983.

[0524] Kriegler et al., Cell, 38:483, 1984a.

[0525] Kriegler et al., Cell, 53:45, 1988.

[0526] Kuhl et al., Cell, 50:1057, 1987.

[0527] Kunz et al., Nucl. Acids Res., 17:1121, 1989.

[0528] Kwoh et al., Proc. Nat'l Acad. Sci. USA, 86: 1173, 1989.

[0529] Ladd et al., Mol. Cell Biol., 21(4):1285-96, 2001.

[0530] Lareyre et al., J. Biol. Chem., 274(12):8282-8290, 1999.

[0531] Larsen et al., Proc Nat'l Acad. Sci. USA., 83:8283, 1986.

[0532] Laspia et al., Cell, 59:283, 1989.

[0533] Latimer et al., Mol. Cell. Biol., 10:760, 1990.

[0534] Laughlin et al., J. Virol., 60(2):515-524, 1986.

[0535] Lawley et al., Ann. Rheum. Dis., 47(6):445-51, 1988.

[0536] Lebkowski et al., Mol. Cell. Biol., 8(10):3988-3996, 1988.

[0537] Lee et al., J. Auton. Nerv. Syst. 74(2-3):86-90, 1997.

[0538] Lee et al., Nature, 294:228, 1981.

[0539] Lee et al., Nucleic Acids Res., 12:4191-206, 1984.

[0540] Levenson et al., Hum Gene Ther, 9(8):1233-6, 1998.

[0541] Levinson et al., Nature, 295:79, 1982.

[0542] Lin and Avery, Nature, 402:128-129, 1999.

[0543] Lin et al., Mol. Cell. Biol., 10:850, 1990.

[0544] Liu et al. Am J Pathol, 158(6):2057-66, 2001.

[0545] Lock et al., Nature Medicine 5:500-508, 2002.

[0546] Lock et al., Nature Medicine 8:500-508, 2002.

[0547] Lopez-Moratalla et al. Nitric Oxide, 1(1):95-104, 1997.

[0548] Lucotte et al., Mult. Scler. 6:78, 2000.

[0549] Luomala et al., Neurology 54:1862, 2000.

[0550] Luria et al., EMBO J., 6:3307, 1987.

[0551] Lusky and Botchan, Proc. Nat'l Acad. Sci. USA, 83:3609, 1986.

[0552] Lusky et al., Mol. Cell. Biol. 3:1108, 1983.

[0553] Macejak and Sarnow, Nature, 353:90-94, 1991.

[0554] Majors and Varmus, Proc. Nat'l Acad. Sci. USA, 80:5866, 1983.

[0555] Maniatis et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1989.

[0556] Mann et al., Cell, 33:153-159, 1983.

[0557] Mann et al., Neurology 54:552, 2000.

[0558] McLaughlin et al., J. Virol., 62(6):1963-1973, 1988.

[0559] McNeall et al., Gene, 76:81, 1989.

[0560] Miksicek et al., Cell, 46:203, 1986.

[0561] Miller et al., Am. J. Clin. Oncol., 15(3):216-221, 1992.

[0562] Miterski et al., Genes Immun. 1:37, 1999.

[0563] Montgomery et al., Proc. Nat'l Acad. Sci. USA, 95:155-2-15507, 1998.

[0564] Mordacq and Linzer, Genes and Dev., 3:760, 1989.

[0565] Moreau et al., Nucl. Acids Res., 9:6047, 1981.

[0566] Mueller and Wold, Science 246, 780-786, 1989.

[0567] Muesing et al., Cell, 48:691, 1987.

[0568] Muller-Ladner et al., J Neurol. Sci., 144(1-2):135-41, 1996.

[0569] Murga et al., Immunity 15; 959-970, 2001.

[0570] Muzyczka, Curr Top Microbiol Immunol, 158:97-129, 1992.

[0571] Mycko et al., Ann. Neurol. 44:70, 1998.

[0572] Mycko et al., J. Neuroimmunol., 84:198, 1998.

[0573] Myhr et al., Neurology 52:1771, 1999.

[0574] Nabel and Baltimore, Nature 326:711-713, 1987.

[0575] Nakamura et al., In: Handbook of Experimental Immunology (4th Ed.), Weir et al., (eds). 1:27, Blackwell Scientific Publ., Oxford, 1987.

[0576] Naldini et al., Science, 272(5259):263-267, 1996.

[0577] Ng et al., Nuc. Acids Res., 17:601, 1989.

[0578] Nicolas and Rubinstein, In: Vectors: A survey of molecular cloning vectors and their uses, Rodriguez and Denhardt, eds., Stoneham: Butterworth, pp. 494-513, 1988.

[0579] Nicolau and Sene, Biochim. Biophys. Acta, 721:185-190, 1982.

[0580] Nicolau et al., Methods Enzymol., 149:157-176, 1987.

[0581] Niino et al., J Neurol. Sci. 179:70, 2000.

[0582] Nomoto et al., Gene, 236(2):259-271, 1999.

[0583] Ohara et al., Proc. Nat'l Acad. Sci. USA, 86: 5673-5677, 1989.

[0584] Omirulleh et al., Plant Mol. Biol., 21:415-28, 1993.

[0585] Ondek et al., EMBO J., 6:1017, 1987.

[0586] Omitz et al., Mol. Cell. Biol., 7:3466, 1987.

[0587] Padberg et al., J. Neuroimmunol., 99(2):218-23, 1999.

[0588] Palmiter et al., Nature, 300:611, 1982.

[0589] Paskind et al., Virology, 67:242-248, 1975.

[0590] PCT Application No. 95/06128

[0591] PCT Application No. WO 94/09699

[0592] PCT Application No. WO 94/09699

[0593] PCT Application PCT/US87/00880

[0594] PCT Application PCT/US89/01025

[0595] PCT Application WO 88/10315

[0596] PCT Application WO 90/07641

[0597] PCT Application WO89/06700

[0598] Pech et al., Mol. Cell. Biol., 9:396, 1989.

[0599] Pelletier and Sonenberg, Nature, 334:320-325, 1988.

[0600] Perales et al., Proc. Nat'l Acad. Sci. USA, 91:4086-4090, 1994.

[0601] Perez-Stable and Constantini, Mol. Cell. Biol., 10:1116, 1990.

[0602] Picard and Schaffner, Nature, 307:83, 1984.

[0603] Pinkert et al., Genes and Dev., 1:268, 1987.

[0604] Plasterk and Ketting, Curr. Opin. Genet. Dev., 10:562-567, 2000.

[0605] Ponta et al., Proc. Nat'l Acad. Sci. USA, 82:1020, 1985.

[0606] Porton et al., Mol. Cell. Biol., 10:1076, 1990.

[0607] Potrykus et al., Mol. Gen. Genet., 199:183-188, 1985.

[0608] Potter et al., Proc. Nat'l Acad. Sci. USA, 81:7161-7165, 1984.

[0609] Queen and Baltimore, Cell, 35:741, 1983.

[0610] Quinn et al., Mol. Cell. Biol., 9:4713, 1989.

[0611] Redondo et al., Science, 247:1225, 1990.

[0612] Reisman and Rotter, Mol. Cell. Biol., 9:3571, 1989.

[0613] Ren et al., Genes Dev., 16: 245-256, 2002.

[0614] Resendez Jr. et al., Mol. Cell. Biol., 8:4579, 1988.

[0615] Rice, Mathematical Statistics and Data Analysis, Duxbury Press, Belmont, CA, 1995.

[0616] Rickert, Oncogene 12: 2631-40, 1996.

[0617] Ridgeway, In: Vectors: A survey of molecular cloning vectors and their uses, Stoneham: Butterworth, pp. 467-492, 1988.

[0618] Ripe et al., Mol. Cell. Biol., 9:2224, 1989.

[0619] Rippe et al., Mol. Cell Biol., 10:689-695, 1990.

[0620] Rittling et al., Nuc. Acids Res., 17:1619, 1989.

[0621] Rosen et al., Cell, 41:813, 1988.

[0622] Roux et al., Proc. Nat'l Acad. Sci. USA, 86:9079-9083, 1989.

[0623] Sakai et al., Genes and Dev., 2:1144, 1988.

[0624] Sambrook et al., In: Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1989.

[0625] Sarchielli et al., J. Neuroimmunol., 80(1-2):76-86, 1997.

[0626] Satake et al., J. Virology, 62:970, 1988.

[0627] Schaffner et al., J. Mol. Biol., 201:81, 1988.

[0628] Searle et al., Mol. Cell. Biol., 5:1480, 1985.

[0629] Sharp and Marciniak, Cell, 59:229, 1989.

[0630] Sharp, Genes Dev., 13:139-141, 1999.

[0631] Sharpand Zamore, Science, 287:2431-2433, 2000.

[0632] Shaul and Ben-Levy, EMBO J, 6:1913, 1987.

[0633] Sherman et al., Mol. Cell. Biol., 9:50, 1989.

[0634] Sleigh and Lockett, J. EMBO, 4:3831, 1985.

[0635] Spalholz et al., Cell, 42:183, 1985.

[0636] Spandau and Lee, J Virology, 62:427, 1988.

[0637] Spandidos and Wilkie, EMBO J, 2:1193, 1983.

[0638] Statistical Toolbox, Math Works, Inc., Version 2.1.1, 1997.

[0639] Stelmasiak et al., Med. Sci. Monit., 7(5): 914-8, 2001.

[0640] Stephens and Hentschel, Biochem. J., 248:1, 1987.

[0641] Storey and Tibshirani, Stanford tech report, 2001.

[0642] Streit et al, J. Invest. Dermatol., 105(4):562-6, 1995.

[0643] Stuart et al., Nature, 317:828, 1985.

[0644] Sullivan and Peterlin, Mol. Cell. Biol., 7:3315, 1987.

[0645] Svenningsson et al., Neurology, 53(8):1880-2, 1999.

[0646] Swartzendruber and Lehman, J. Cell. Physiology, 85:179, 1975.

[0647] Tabara et al., Cell, 99:123-132, 1999.

[0648] Takebe et al., Mol. Cell. Biol., 8:466, 1988.

[0649] Takiguchi et al., Am. J. Physiol., 274(2 Pt 1):E265-70, 1998.

[0650] Tavernier et al., Nature, 301:634, 1983.

[0651] Taylor and Kingston, Mol. Cell. Biol., 10: 165, 1990a.

[0652] Taylor and Kingston, Mol. Cell. Biol., 10:176, 1990b.

[0653] Taylor et al., J. Biol. Chem., 264:15160, 1989.

[0654] Temin, In: Gene Transfer, Kucherlapati (ed.), New York: Plenum Press, pp. 149-188, 1986.

[0655] Thiesen et al., J. Virology, 62:614, 1988.

[0656] Thomas, Genome Research 11, 1227-1236, 2001.

[0657] Tienari et al., Lancet 340:987-91, 1992.

[0658] Tratschin et al., Mol. Cell. Biol., 4:2072-2081, 1984.

[0659] Treisman, Cell, 42:889, 1985.

[0660] Tronche et al., Mol. Biol. Med., 7:173, 1990.

[0661] Trudel and Constantini, Genes and Dev. 6:954, 1987.

[0662] Tsumaki et al., J. Biol. Chem. 273(36):22861-22864, 1998.

[0663] Tur-Kaspa et al., Mol. Cell Biol., 6:716-718, 1986.

[0664] Tusher et al., Proc. Nat'l Acad. Sci. USA 98, 5116-5121, 2001.

[0665] Two tailed t-test: www.psycho.uni-duesseldorf.de/aap/proj ects/gpower/reference/

[0666] Tyndell et al., Nuc. Acids. Res., 9:6231, 1981.

[0667] Vandenbroeck et al., Genes Immunol 1:460, 2000.

[0668] Vandenbroeck et al., J. Neuroimmunol. 76:189, 1997.

[0669] Vannice and Levinson, J. Virology, 62:1305, 1988.

[0670] Vasseur et al., Proc Nat'l Acad. Sci. U.S.A., 77:1068, 1980.

[0671] Wagner et al., Proc. Nat'l Acad. Sci. USA 87(9):3410-3414, 1990.

[0672] Wagner et al., Science, 260:1510-1513, 1993.

[0673] Walker et al., Proc. Nat'l Acad. Sci. USA, 89:392-396 1992.

[0674] Walter et al., J. Clin. Invest. 87:1266, 1991.

[0675] Wang and Calame, Cell, 47:241, 1986.

[0676] Warrington et al., Physiol. Genomics 2: 143-7, 2000.

[0677] Weber et al., Cell, 36:983, 1984.

[0678] Weinberger et al., Mol. Cell. Biol., 8:988, 1984.

[0679] Wilson et al., Science, 244:1344-1346, 1989.

[0680] Winer et al., J. Immunol., 166(7):4751-6, 2001.

[0681] Winoto and Baltimore, Cell 59:649, 1989.

[0682] Wong et al., Gene, 10:87-94, 1980.

[0683] Wu and Wu, J. Biol. Chem., 262:4429-4432, 1987.

[0684] Wu and Wu, Adv. Drug Delivery Rev., 12:159-167, 1993.

[0685] Wu and Wu, Biochemistry, 27:887-892, 1988.

[0686] Wu et al., Nature 414(6862):457-62, 2001.

[0687] Wu et al, Biochem Biophys Res Commun., 233(1):221-226, 1997.

[0688] Yamashita et al, J Neurol. Sci., 153(1):32-4, 1997.

[0689] Yang et al., Proc. Nat'l Acad. Sci. USA, 87:9568-9572, 1990.

[0690] Yuceyar et al., Clin. Neurol. Neurosurg., 103(4):206-11, 2001.

[0691] Yutzey et al., Mol. Cell Biol., 9:1397, 1989.

[0692] Zhao-Emonet et al, Biochem. Biophys. Acta., 1442(2-3):109-19, 1998.

[0693] Zufferey et al, Nat. Biotechnol., 15(9):871-875, 1997.

Claims

1. A method of predicting whether a subject is or will be afflicted with multiple sclerosis (MS) comprising: (a) obtaining an mRNA-containing sample from said subject; (b) determining expression information for one or more genes from the group consisting of phosphatidylinositol transfer protein, inducible nitric oxide synthase, CIC-1 muscle chloride channel protein, placental bikunin, receptor kinase ligand LERK-3, GATA-4, thymopoietin, transcription factor E2f-2, S-adenosylmethionine synthetase, carcinoembryonic antigen, ret transforming gene, G protein-linked receptor, GTP-binding protein RALB, tyrosine kinase Syk, T cell leukemia LERK-2, tyrosine kinase (ELK1) oncogene, transcription factor SL1, phospholipase c, gastricsin, and D13S824E locus; (c) comparing expression information for said selected genes with the expression information of the same genes in a subject not afflicted with MS; and (d) predicting whether said subject is or will be afflicted with MS.

2. The method of claim 1, wherein the expression information for more one gene in the group of claim 1(b) is determined.

3. The method of claim 1, wherein the expression information for at least 2 genes in the group of claim 1(b) is determined.

4. The method of claim 1, wherein the expression information for at least 3 genes in the group of claim 1(b) is determined.

5. The method of claim 1, wherein the expression information for at least 4 genes in the group of claim 1(b) is determined.

6. The method of claim 1, wherein the expression information for at least 5 genes in the group of claim 1(b) is determined.

7. The method of claim 1, wherein the expression information for at least 6 genes in the group of claim 1(b) is determined.

8. The method of claim 1, wherein the expression information for at least 7 genes in the group of claim 1(b) is determined.

9. The method of claim 1, wherein the expression information for at least 8 genes in the group of claim 1(b) is determined.

10. The method of claim 1, wherein the expression information for at least 9 genes in the group of claim 1 (b) is determined.

11. The method of claim 1, wherein the expression information for 10-20 genes in the group of claim 1(b) is determined.

12. The method of claim 1, wherein said sample comprises peripheral blood-derived mononuclear cells.

13. The method of claim 1, further comprising determining expression information for an additional one or more genes in Tables 1, 4, 7, and 10.

14. The method of claim 1, further comprising determining expression information for one or more genes in Tables 2, 5, 8, and 11.

15. The method of claim 1, further comprising determining expression information for one or more genes in Tables 3, 6, 9, and 12.

16. The method of claim 1, further comprising obtaining expression information for each gene in step (b) from a subject not afflicted with MS.

17. The method of claim 1, wherein expression information is determined by microarray analysis of mRNA transcripts.

18. The method of claim 1, wherein expression information is determined by multiplex PCR of transcripts, northern blot, quantitative real time PCR, reverse trancription PCR (RT-PCR), or RNAse protection.

19. The method of claim 1, wherein expression information is determined by immunohistochemistry, ELISA or western blot.

20. The method of claim 17, wherein microarray analysis comprises use of oligonucleotides that hybridize to mRNA transcripts or cDNAs for the selected genes, and wherein the oligonucleotides are disposed or directly synthesized on the surface of a chip or wafer.

21. The method of claim 20, wherein said oligonucleotides are about 10 to about 50 base pairs in length.

22. A chip or wafer comprising a nucleic acid microarray, wherein said nucleic acids hybridize to target transcripts or cDNAs for phosphatidylinositol transfer protein, inducible nitric oxide synthase, CIC-1 muscle chloride channel protein, placental bikunin, receptor kinase ligand LERK-3, GATA-4, thymopoietin, transcription factor E2f-2, S-adenosylmethionine synthetase, carcinoembryonic antigen, ret transforming gene, G protein-linked receptor, GTP-binding protein RALB, tyrosine kinase Syk, T cell leukemia LERK-2, tyrosine kinase (ELK1) oncogene, transcription factor SL1, phospholipase c, gastricsin, and D13S824E locus.

23. The chip of claim 22, wherein said chip is comprised of polymers, plastics, resins, polysaccharides, silica or silica-based materials, fiberoptic materials, carbon, metals, inorganic glasses, or nitrocellulose.

24. The chip of claim 22, wherein said nucleic acids are cDNAs.

25. The chip of claim 22, wherein said nucleic acids are oligonucleotides.

26. The chip of claim 22, wherein said oligonucleotides are about 10 to about 50 base pairs or less in length.

27. A method for monitoring a therapy for multiple sclerosis comprising: (a) obtaining an mRNA-containing sample from a subject receiving said therapy; (b) determining expression information for one or more genes comprising phospatidylinositol transfer protein, inducible nitric oxide synthase, CIC-1 muscle chloride channel protein, placental bikunin, receptor kinase ligand LERK-3, GATA-4, thymopoietin, transcription factor E2f-2, S-adenosylmethionine synthetase, carcinoembryonic antigen, ret transforming gene, G protein-linked receptor, GTP-binding protein RALB, tyrosine kinase Syk, T cell leukemia LERK-2, tyrosine kinase (ELK1) oncogene, transcription factor SL1, phospholipase c, gastricsin, and D13S824E locus; and (c) comparing expression information for said selected genes with the expression information of the same genes in an MS subject not receiving said therapy.

28. The method of claim 27, further comprising determining expression information for an additional one or more genes in Tables 1, 4, 7, and 10.

29. The method of claim 27, further comprising determining expression information for one or more genes in Tables 2, 5, 8, and 11.

30. The method of claim 27, further comprising determining expression information for one or more genes in Tables 3, 6, 9, and 12.

31. The method of claim 27, wherein said sample is peripheral blood.

32. The method of claim 27, further comprising modifying said therapy based upon the altered expression of one or more of said selected genes.

33. The method of claim 27, further comprising making a prediction on the efficacy of treating the subject from which said sample was obtained.

34. The method of claim 27, wherein the expression information is determined by microarray analysis of transcripts.

35. The method of claim 27, wherein the expression information is determined by multiplex PCR of transcripts, northern blot, quantitative real time PCR, reverse trancription PCR (RT-PCR), or RNAse protection.

36. The method of claim 27, wherein the expression information is determined by immunohistochemistry, western blot or ELISA.

37. The method of claim 34, wherein microarray analysis comprises use of oligonucleotides that hybridize to transcripts or cDNAs for the selected genes, and wherein the oligonucleotides are disposed or synthesized directly on the surface of a chip or wafer.

38. The method of claim 37, wherein said chip is comprised of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose.

39. The method of claim 37, wherein said oligonucleotides are about 10 to about 50 base pairs or less in length.

40. The method of claim 27, wherein said MS subject not receiving said therapy is the same subject prior to receiving said therapy.

41. The method of claim 27, further comprising determining expression information for said selected genes from said subject at multiple time points.

42. A method for determining the efficacy of a therapy for multiple sclerosis comprising: (a) obtaining an mRNA-containing sample from a subject receiving said therapy; (b) determining expression information for one or more selected genes selected from the group consisting of skeletal muscle LIM-prot SLIM1, R kappa B, 815A9.1 myosin heavy chain, γ G2 psi from γ crystallin, thrombospondin 4, KIAA0178 (or Z97054); (c) comparing expression information for said one or more selected genes with the expression information of the same gene or genes in an MS subject not receiving said therapy; and (d) determining the efficacy of said therapy based on the ability of said therapy to alter the expression of said one or more genes.

43. The method of claim 42, further comprising determining expression information for one or more genes in Table 14.

44. The method of claim 43, further comprising determining expression information for one or more genes in Table 15.

45. A method for treating multiple sclerosis (MS) comprising administering to a subject with MS a drug that causes an increase in the level of a gene product selected from the group consisting of those genes indicated by a minus (−) sign in Tables 1-12.

46. A method for treating multiple sclerosis (MS) comprising administering to a subject with MS a drug that causes a decrease in the level of a gene product selected from the group consisting of those genes indicated by a plus (+) sign in Tables 1-12 and 16.