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

Effie W. Petersdorf1,2,*, Mari Malkki1, Theodore A. Gooley1, Stephen R. Spellman3, Michael D. Haagenson3, Mary M. Horowitz4,5 and Tao Wang6

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.