title: Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation.
abstract: 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.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. epetersd@fhcrc.org
authors.forename: Effie W
authors.initials: EW
authors.lastname: Petersdorf
authors.forename: Mari
authors.initials: M
authors.lastname: Malkki
authors.forename: Mary M
authors.initials: MM
authors.lastname: Horowitz
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Spellman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Haagenson
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000209:etiology / Q000401:mortality*; D006239:Haplotypes / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics / Q000401:mortality* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000209:etiology / Q000401:mortality*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D014184:Transplantation, Homologous; D061349:Unrelated Donors / Q000706:statistics & numerical data; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm