MHC-Resident Variation Affects Risks After Unrelated Donor Hematopoietic Cell Transplantation

The success of HLA-matched unrelated donor hematopoietic cell transplantation depends on non-HLA MHC region genetic variation. SNPing Away at Graft-Versus-Host Disease The major histocompatibility complex (MHC) governs the acceptance or rejection of grafts. Donor-recipient matching of human leukocyte antigens (HLAs), which are found in the MHC, is critical not only to prevent transplant rejection but also to limit graft-versus-host disease (GVHD)—a side effect of blood cell transplant where the donor blood cells attack the recipient. GVHD is the leading cause of early complications and death after unrelated donor hematopoietic cell transplantation Transplants from related donor are preferred, because up to 80% of recipients of fully HLA-matched, but unrelated, donors develop GVHD. Now, Petersdorf et al. identify single-nucleotide polymorphisms (SNPs) within the MHC, but not in the HLA, that may contribute to the development of GVHD. The authors scanned more than 4000 samples in HLA-matched donor-recipient pairs for MHC region SNPs that were not in the HLA. Outcome did not depend on the total number of SNPs; rather, specific SNPs contributed disproportionately. Of these, two SNPs were markers of disease-free survival and acute GVHD. Moreover, on the basis of the currently available donor pool, recipients may be able to further match SNPs before transplant to decrease their risk of GVHD. Thus, non-HLA SNP screening could improve patient outcome after hematopoietic transplantation. Blood malignancies can be cured with hematopoietic cell transplantation from human leukocyte antigen (HLA)–matched unrelated donors; however, acute graft-versus-host disease (GVHD) affects up to 80% of patients and contributes to increased mortality. To test the hypothesis that undetected patient-donor differences for non-HLA genetic variation within the major histocompatibility complex (MHC) could confer risks after HLA-matched transplantation, we conducted a discovery-validation study of 4205 transplants for 1120 MHC region single-nucleotide polymorphisms (SNPs). Two SNPs were identified as markers for disease-free survival and acute GVHD. Among patients with two or more HLA-matched unrelated donors identified on their search, SNP genotyping of patients and their potential donors demonstrated that most patients have a choice of SNP-matched donors. In conclusion, the success of HLA-matched unrelated donor hematopoietic cell transplantation depends on non-HLA MHC region genetic variation. Prospective SNP screening and matching provides an approach for lowering risks to patients.