Research Project
6647744
DESCRIPTION (provided by applicant): Beta-thalassemias are extremely common in SouthEast Asia. Many of the molecular defects accounting for the beta-chain deficiencies in these patients have been characterized, and are attributed to adult beta-globin gene mutations resulting in reduced levels (beta+-thalassemia) or complete inactivation (beta0-thalassemia) of the encoded beta-chains. The great numbers of individuals with thalassemia trait or disease have overwhelmed the medical service communities in this region, where the expense and/or limited availability precludes access to needed resources for many if not most of the patients. Due to recent worldwide migrations, these abnormal alleles and associated disorders are becoming more common in other regions, including the U.S. One mutant allele, HbE, identified as a G>A substitution in codon 26 of beta-globin, may be the most common beta-thalassemia allele worldwide. This allele is unusual in that it combines two forms of deficiency: one is qualitative, in that this substitution leads to a Glu>Lys amino acid change in the encoded protein, and the other is quantitative, in that the mutation alters normal splicing. A most puzzling feature of HbE is the variable disease presentation in heterozygotes with another beta-thalassemia allele, for example in beta0-thalassemia/ HbE disorder. Patients with seemingly identical "functional genotypes" at this locus, i.e. expression only of betaE-globin from one allele, show a remarkable variability in disease severity, ranging from nearly asymptomatic (MILD disease) to transfusion-dependent anemia with additional complications (SEVERE disease). There exists a great and immediate need to identify the modifying factors, which may represent either novel therapeutic targets or the focus of diagnostic assays to help identify at-risk individuals. To address this need, we intend to perform a genomewide search for genetic polymorphisms associated with disease severity. SEQUENOM's platform for genetic analysis, DNA MassArray, has been developed to provide accurate and high throughput scoring of genetic variations in a highly automated setting. We intend to test the feasibility of genomwide association studies by taking a "brute-force", unbiased approach to identifying modifiers of severity in patients with beta 0-thalassemia/HbE disease. It's anticipated this "non-hypothesis-driven" approach may also reveal genes that might have been overlooked because of expectations based on current understanding of biology. To our knowledge, using 100,000 gene-based SNPs, this will be the largest genomewide association study ever undertaken in an attempt to identify disease susceptibility or protective alleles.
