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MHC-resident variation affects risks after unrelated donor hematopoietic cell transplantation.

ABSTRACT: 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.

SUBMITTER: Petersdorf EW

PROVIDER: S-EPMC3633562 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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MHC-resident variation affects risks after unrelated donor hematopoietic cell transplantation.

Petersdorf Effie W EW Malkki Mari M Gooley Theodore A TA Spellman Stephen R SR Haagenson Michael D MD Horowitz Mary M MM Wang Tao T

Science translational medicine 20120701 144

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 ...[more]

PMID: 22837536

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Project description:BackgroundIdentification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.MethodsWe performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011.FindingsUsing meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10-8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p = 3.3 × 10-8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p = 2.0 × 10-8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p = 3.15 × 10-8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p = 2.84 × 10-8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p = 6.9 × 10-9) and CT49 (rs32250, HR = 1.44, 95% CI1.26-1.64, p = 2.6 × 10-8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p = 1.26 × 10-8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p = 4.6 × 10-9). Results publicly available at https://fuma.ctglab.nl/browse.InterpretationThese data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies.FundingThis project was funded by grants from the National Institutes of Health, USA.

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MHC-resident variation affects risks after unrelated donor hematopoietic cell transplantation.

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MHC-resident variation affects risks after unrelated donor hematopoietic cell transplantation.

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