Research Project
10248324
Survival rates after hematopoietic cell transplantation depend on the ancestry of the patient. Patients of African-American heritage have lower overall rates of survival after transplantation compared to patients of other backgrounds. The underlying immunobiological factors that contribute to survivorship disparities in transplantation are not known. We recently discovered that patients whose inherited germlines encode certain amino acid substitutions in the HLA-DR? protein are at high-risk of mortality; these DR? proteins are found at highest frequency in African American populations, and provide a basis for understanding the role of germline variation as factors for clinical outcome. We propose that the extended high and low-risk HLA haplotypes encode undetected variation that contributes to survivorship disparities. The specific aims are to: define the content and phase of coding and non-coding regions of HLA class I and III genes; determine the impact of coding and non-coding variation on gene expression; determine the clinical significance of class I and III genes and haplotypes in HCT, and determine the risks associated with HLA mismatching. This proposal will fill the knowledge gap in the immunobiological basis of survivorship disparities in transplantation. The information will increase the safety, efficacy and availability of transplantation for all patients in need of this life-saving therapy.
