Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation

• Published in: Blood 2013-03, Vol.121 (10), p.1896-1905
• Main Authors: Petersdorf, Effie W., Malkki, Mari, Horowitz, Mary M., Spellman, Stephen R., Haagenson, Michael D., Wang, Tao
• Format: Article
• Language: English
• Subjects: Acute Disease; Adolescent; Adult; Biomarkers, Tumor - metabolism; Child; Child, Preschool; Chronic Disease; DNA, Neoplasm - genetics; Female; Genotype; Graft vs Host Disease - etiology; Graft vs Host Disease - mortality; Haplotypes - genetics; Hematologic Neoplasms - genetics; Hematologic Neoplasms - mortality; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation - adverse effects; Histocompatibility Testing; Humans; Infant; Infant, Newborn; Major Histocompatibility Complex - genetics; Male; Neoplasm Recurrence, Local - etiology; Neoplasm Recurrence, Local - mortality; Polymerase Chain Reaction; Polymorphism, Single Nucleotide - genetics; Prognosis; Retrospective Studies; Survival Rate; Transplantation; Transplantation, Homologous; Unrelated Donors - statistics & numerical data; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-11-465161

Life-threatening risks associated with HLA-mismatched unrelated donor hematopoietic cell transplantation limit its general application for the treatment of blood diseases. The increased risks might be explained by undetected genetic variation within the highly polymorphic major histocompatibility complex (MHC) region. We retrospectively assessed each of 1108 MHC region single nucleotide polymorphisms (SNPs) in 2628 patients and their HLA-mismatched unrelated donors to determine whether SNPs are associated with the risk of mortality, disease-free survival, transplant-related mortality, relapse, and acute and chronic graft-versus-host disease (GVHD). Multivariate analysis adjusted for HLA mismatching and nongenetic variables associated with each clinical end point. Twelve SNPs were identified as transplantation determinants. SNP-associated risks were conferred by either patient or donor SNP genotype or by patient-donor SNP mismatching. Risks after transplantation increased with increasing numbers of unfavorable SNPs. SNPs that influenced acute GVHD were independent of those that affected risk of chronic GVHD and relapse. HLA haplotypes differed with respect to haplotype content of (un)favorable SNPs. Outcome after HLA-mismatched unrelated donor transplantation is influenced by MHC region variation that is undetected with conventional HLA typing. Knowledge of the SNP content of HLA haplotypes provides a means to estimate risks prior to transplantation and to lower complications through judicious selection of donors with favorable MHC genetics. •HLA haplotypes encode single nucleotide polymorphisms (SNPs) that are associated with risks after HLA-mismatched unrelated donor HCT.•SNPs associated with graft-versus-host disease (GVHD) are independent of those associated with relapse.