Genome-Wide Association Study of Genetic Susceptibility for Graft-vs-Host Disease Cohort 1

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative therapy for many advanced hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues, and initiating an alloimmune response resulting in damage to many organs including the skin, gastrointestinal (GI) tract, and liver in recipient. More than half of all Allo-HSCT recipients develop different degrees of GVHD (grades I-IV). About 20% of recipients develop severe GVHD (grades III-IV) that is associated with a very high morbidity and mortality. The most important factor determining the severity of GVHD is the genetic disparities between donors and recipients, as is reflected in human leukocyte antigen (HLA) haplotypes that are routinely checked for donor selection. Even when donors and recipients are HLA-identical, many recipients develop severe GVHD. As a result, non-HLA antigens are important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence of an interaction between antigens present in one individual with the immune system of another individual. As a result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide Association Studies (GWAS) in 3,000 patients who underwent Allo-HSCT and in their respective donors (6000 DNA samples) that are provided to us by the Center for International Blood and Marrow Transplant Research (CIBMTR), a research collaboration between the NMDP and Medical College of Wisconsin. In the second aim, we will validate the association between high risk genotypes detected in the first aim and severe GVHD in 1,750 donors and 1,750 recipients of Allo-HSCT, and perform the joint analysis with the discovery samples. In the third aim, we will investigate the functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD in mixed lymphocyte reaction (MLR), as an ex vivo surrogate for an alloimmune response.]]>
Inclusion Criteria: First allogeneic transplants were done between January 1, 2000-July 29, 2004 and July 30, 2007-July 29, 2014, with peripheral blood stem cells or bone marrow where primary disease and indication for transplant were for acute lymphoblastic leukemia, acute myelogenous leukemia, or myelodysplastic syndrome. All cases were retrospectively HLA typed through the ongoing NMDP typing program utilizing pre-transplant research samples stored in the CIBMTR Research Sample Repository. The donor/recipient match was verified as 8/8 or 7/8 high resolution of HLA matched considering HLA-A, -B, -C and -DRB1 genes. Longitudinal outcome data was reported to the CIBMTR on the comprehensive report forms. All cases had DNA samples available for whole genome genotyping. Exclusion Criteria: Cases included in DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one Year mortality after BMT) (NHLBI: 1R01HL102278)Patients receiving ex vivo T cell depleted grafts, post- transplant-Cyclophosphamide or missing data on graft vs host disease prophylaxis]]>
Discovery cohort uploaded in Aug. 2021Validation cohort initial uploaded in Oct. 2022. Files to be revised as needed following CIDR data cleaning completion.]]>