Abstract
BackgroundCurrent criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined.Methods and FindingsWe isolated DNA strands extending across 2 million base pairs of the MHC to determine the physical linkage of HLA-A, -B, and -DRB1 alleles in 246 HCT recipients and their HLA-A, -B, -C, -DRB1, -DQB1 allele-matched unrelated donors. MHC haplotype mismatching was associated with a statistically significantly increased risk of severe acute GVHD (odds ratio 4.51; 95% confidence interval [CI], 2.34–8.70, p < 0.0001) and with lower risk of disease recurrence (hazard ratio 0.45; 95% CI, 0.22–0.92, p = 0.03).ConclusionsThe MHC harbors genes that encode unidentified transplantation antigens. The three-locus HLA-A, -B, -DRB1 haplotype serves as a proxy for GVHD risk among HLA-identical transplant recipients. The phasing method provides an approach for mapping novel MHC-linked transplantation determinants and a means to decrease GVHD-related morbidity after HCT from unrelated donors.
Highlights
A hallmark of the human genome is its organization into segments or blocks of closely linked genetic variants that are inherited as haplotypes on the same DNA strand of a chromosome [1,2]
human leukocyte antigen (HLA)-A, -B, -DRB1 haplotype serves as a proxy for Graft-versus-host disease (GVHD) risk among HLA-identical transplant recipients
The phasing method provides an approach for mapping novel major histocompatibility complex (MHC)-linked transplantation determinants and a means to decrease GVHD-related morbidity after hematopoietic cell transplantation (HCT) from unrelated donors
Summary
A hallmark of the human genome is its organization into segments or blocks of closely linked genetic variants that are inherited as haplotypes on the same DNA strand of a chromosome [1,2]. Intense efforts are in progress to define the linkage of SNPs in genomic DNA, to specify the organization of SNPs into haplotype blocks, and to identify the SNPs that could serve as proxies for haplotype blocks (tagSNPs) [4,5] This information provides powerful tools for mapping genes that cause disease [6]. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined. GVHD and graft rejection occur most often in people who receive transplants from unrelated donors because, when donors are matched to recipients matching is done for the most important HLA antigens known to be involved, it has not technically been possible to match for all possible antigens. If it were possible to better map the structure of this region, it would be possible to better match recipients and donors (especially unrelated donors) for the unidentified transplantation antigens and reduce the chance of recipients getting GVHD or rejecting their grafts
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