Genetic Mechanisms of Survivorship Disparities after Unrelated HCT

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DESCRIPTION (provided by applicant): Patients suffering from leukemia can be cured with unrelated hematopoietic cell transplantation (HCT). We discovered that survival after unrelated HCT strongly depends on the patient's ethnicity. African American (AFA) patients had significantly increased risk of mortality and Asian (API) patients had increased risk of relapse and decreased risk of graft-versus-host disease, when compared to Caucasian (CAU) patients. We identified a role for 1L1A, ILIB, IL6, and IL15RA gene variation in outcome and hypothesize that the survival disparities are in part due to ancestry-related differences in the frequencies of at-risk IRG alleles and haplotypes. Current information on IRG haplotype diversity is hampered by the lack of robust tools for definitive phase assignment. Investigation into the mechanisms through which IRG diversity impacts survival after HCT also requires precise definition of the race of the transplant patient and donor. As AFA and API individuals have known admixture, application of ancestry-informative markers (AIMs) for measuring admixture will greatly facilitate the study of genetic mechanisms of survivorship disparities. The specific aims of this proposal are to 1) Determine ILIA, ILIB, IL1RN, IL6, IL6R, ILI 5 and 1L15RA sequence variation and its organization on haplotypes in individuals of AFA, API, CAU ancestry as defined by AIMs; 2) define the phylogeny of ILIA, ILIB, IL1RN, IL6, IL6R, IL15 and IL15FiA haplotypes in cades; 3) define SNP, haplotype, and clad-based mechanisms of GVHD, GVL and survival in AFA, API and CAU transplant patients, and 4) determine the impact of IRG variation on gene expression in healthy individuals. This new application is the first of its kind to interrogate the genetic mechanisms for survivorship disparities in transplantation, using a novel haplotype phasing tool and AIMs for assignment of ancestry. The information will aid efforts to optimize transplant outcomes for AFA and API patients, while creating a highly novel and unique resource for continued investigation into the genetic basis of disease. PUBLIC HEALTH RELEVANCE: Transplantation of blood stem cells from a healthy unrelated donor can cure patients of leukemia and other types of blood cancers. Survival after transplantation is strongly influenced by the ancestry of the patient. We will define the ways in which the genetic code places patients of different ancestry at risk. We hope the information will help patients and physicians plan the best kinds of therapy for blood cancers in the future.