The goal of this R01 proposal is to identify genetic variants that affect complications and risks of 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 enlarge the existing discovery cohort to significantly increase power for detecting additional genetic variants associated with HCT outcomes;(2) perform an in silico candidate gene study using the GWAS-HCT database to replicate results of previously published studies;and (3) develop an innovative approach to i) measuring genome-wide genetic disparity between donor and recipient, and using this measure to test for association with GVHD, relapse and mortality, and ii) identifying non-MHC loci encoding minor histocompatibility antigens that serve as the targets for GVHD and the graft-vs-leukemia (GVL) effect. The current research effort will represent an extension of a GWAS-HCT we initiated in 2006 with the support of R01 HL087690 (09/25/2006-07/31/2009) which generated genome scans for 1,553 HCT cases (>3,000 patient and donor samples) using the Affymetrix 5.0 GeneChip. Analyses thus far have revealed associations with loci conferring risks of 2-fold or greater. However, effects below this threshold, which may identify many more novel pathogenic pathways, require greater statistical power. The first specific aim is to expand the GWAS-HCT project to include all patients transplanted at our Center from 1988 through 2009, bringing the total number to ~5,000 transplants (~10,000 patients and donors). Increasing the sample size by >300% will improve power for detecting genetic variants associated with HCT outcomes across a range of odds as low as 1.5, and provide opportunity for including additional high priority but low incidence clinical phenotypes that occur in this patient population with a frequencies as low as 10-15%. The HCT outcomes phenotypes analyzed will include acute and chronic GVHD, immunological tolerance, airflow obstruction (AFO disease/bronchiolitis obliterans syndrome (BOS), acute kidney injury (AKI), Gram negative bacteremia, invasive fungal disease, CMV infection and disease, disease relapse and transplant-related mortality. 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.

Public Health Relevance

We propose performing a genome-wide association study (GWAS) of hematopoietic cell transplant (HCT) outcomes to determine why overall results and complications vary from patient to patient. The proposed study is designed to indentify genetics polymorphisms associated with the risk and severity of acute and chronic graft-versus-host disease (GVHD), organ toxicity, opportunistic infection and overall survival. The study will include 5,000 transplant cases (10,000 patients and donors). Genetic variants associated with HCT outcome will be validated as markers for assessing risk prior to transplant, counseling, treatment planning. 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL105914-01
Application #
8022984
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Di Fronzo, Nancy L
Project Start
2011-01-01
Project End
2014-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
1
Fiscal Year
2011
Total Cost
$2,445,048
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
DeWitt 3rd, William S; Smith, Anajane; Schoch, Gary et al. (2018) Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity. Elife 7:
Fisher, Cynthia E; Hohl, Tobias M; Fan, Wenhong et al. (2017) Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation. Blood 129:2693-2701
Martin, Paul J; Levine, David M; Storer, Barry E et al. (2017) Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood 129:791-798
Inamoto, Yoshihiro; Martin, Paul J; Flowers, Mary E D et al. (2016) Genetic risk factors for sclerotic graft-versus-host disease. Blood 128:1516-24
Martin, Paul J; Fan, Wenhong; Storer, Barry E et al. (2016) Replication of associations between genetic polymorphisms and chronic graft-versus-host disease. Blood 128:2450-2456
Leger, Kasey J; Cushing-Haugen, Kara; Hansen, John A et al. (2016) Clinical and Genetic Determinants of Cardiomyopathy Risk among Hematopoietic Cell Transplantation Survivors. Biol Blood Marrow Transplant 22:1094-1101
Zhao, Lue Ping; Fan, Wenhong; Goodman, Gary et al. (2015) Deciphering Genome Environment Wide Interactions Using Exposed Subjects Only. Genet Epidemiol 39:334-46
Warren, E H; Deeg, H J (2013) Dissecting graft-versus-leukemia from graft-versus-host-disease using novel strategies. Tissue Antigens 81:183-93
Chien, Jason W; Zhang, Xinyi Cindy; Fan, Wenhong et al. (2012) Evaluation of published single nucleotide polymorphisms associated with acute GVHD. Blood 119:5311-9
Warren, Edus H; Zhang, Xinyi Cindy; Li, Shuying et al. (2012) Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT. Blood 120:2796-806

Showing the most recent 10 out of 11 publications