The goal of this R01 proposal is to identify single nucleotide polymorphisms (SNPs) that are associated with complications after allogeneic hematopoietic cell transplant (HCT). Validated discoveries will provide the information necessary to greatly improve risk assessment, counseling, treatment planning and to direct future mechanistic studies of the genes and pathways that control the complex post-HCT phenotypes thereby providing insight and rationale for new targeted therapies. The immediate objectives of this proposal are (1) to perform GWAS discovery studies to identify genetic variants associated with significant outcomes after HCT discovery and replication GWAS of the expanded data set; (2) to test SNP alleles that are mismatched in the recipient and are known or proposed to encode minor histocompatibility antigens associated with GVHD- related outcomes after HCT; and (3) perform an in silico candidate gene studies to replicate results of previously published studies from the HCT literature and the NHGRI GWAS Catalog. genome-wide for 9,118 patients and donors. The HCT outcomes phenotypes analyzed will include acute and chronic GVHD, acute kidney injury (AKI), immunologic tolerance, Gram negative bacteremia, invasive fungal disease, CMV infection and disease, disease relapse, nonrelapse mortality and overall survival. We will also apply an innovative approach to the analysis of recipient-donor genetic disparity to identify the minor histocompatibility genes responsible for GVHD and the graft-vs-leukemia (GVL) effect. This comprehensive genetic and rich phenotype data will be available through dbGaP, and will provide a novel opportunity for leveraging HCT genetics for the broader improvement of HCT safety and efficacy.
We propose performing a genome-wide association study (GWAS) of hematopoietic cell transplant (HCT) outcomes to determine the genetic basis for why overall results and complications vary from patient to patient. The proposed study is designed to indentify genetic polymorphisms associated with the risk and severity of acute and chronic graft-versus-host disease (GVHD), organ toxicity, opportunistic infection, the development of immunological tolerance, nonrelapse mortality, relapse and overall survival. Genetic variants associated with HCT outcome may have utility for assessing risk prior to transplant, counseling and treatment planning, and the genes and pathways discovered will provide mechanistic insight into the disease processes responsible for these complications and the rationale for developing novel targeted therapies for preventing and controlling these complications in the future.
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