Assessment of HLA-B Genetic Variation with an HLA-B Leader Tool and Implications in Clinical Transplantation

Abstract

Sequence variation in the HLA-B gene is critically linked to differential immune responses. A dimorphism at -21 of HLA-B exon 1 gives rise to leader peptides that are markers for risk of acute graft-versus-host disease (GVHD), relapse, and mortality after unrelated donor and cord blood transplantation. To optimize the selection of stem cell transplant sources based on the HLA-B leader, an HLA-B Leader Assessment Tool ("BLEAT") was developed to automate the assignment of leader genotypes, define HLA-B leader match statuses, and rank order candidate stem cell sources according to clinical risk. The base cohort consisted of 9,417,614 registered donors from the Be The Match Registry® with HLA-B typing. Among these donors, the performance of BLEAT was assessed in 1,098,358 donors with sequence data for HLA-B exon 1 (2,196,716 haplotypes). The accuracy of leader assignment was then assessed in a second cohort of 1,259 patients and their unrelated transplant donors. We furthermore established the frequencies of HLA-B leader genotype (MM, MT, TT) representations in broad racial categories in the 9.42 million donors. BLEAT has direct applications for the selection of optimal stem cell sources for transplantation and broad utility in basic and clinical research in pharmacogenomics, vaccine development, and cancer and infectious disease studies of human populations.

HLA informs risk predictions after haploidentical stem cell transplantation with posttransplantation cyclophosphamide

“…The assignment of the HLA-B leader furthermore requires no additional testing of the locus, and new tools are available to automate the assignment of the leader to each allele. 47 When multiple haploidentical family members are available, our results may be applied to prioritize the donor providing the highest likelihood of a successful transplant. With prospective consideration of HLA-B leader matching and HLA-DRB1 mismatching, the proportion of transplants with both favorable features is likely to greatly increase the 50% observed in the current study.…”

HLA‐B leader genotypes in a clinical population

“…With the availability of the online BLEAT tool, direct observation of rs1050458 may not be necessary unless the typing suggests the presence of a novel HLA‐B allele; in this situation, analysis of the exon 1 SNP that is linked to the novel allele may provide confirmation that the leader peptide of the new allele is consistent with that of the parent antigen. Alternatively, a novel allele might be linked to the alternative SNP allele 11 . There are still many alleles with incomplete sequencing data for exon 1; however, the lack of exon 1 data does not preclude assignment of the leader because of the strong positive LD between exon 1 and first field typing data 11 .…”

“…Alternatively, a novel allele might be linked to the alternative SNP allele 11 . There are still many alleles with incomplete sequencing data for exon 1; however, the lack of exon 1 data does not preclude assignment of the leader because of the strong positive LD between exon 1 and first field typing data 11 . As noted by Sajulga et al, the HLA‐B leader may differ among certain ambiguous combinations defined by their G group assignment 11 …”

“…[6][7][8][9][10] Although rs1050458-A/C/G/T substitutions are annotated in the GeneView database, the two alleles found worldwide are rs1050458-C/T. [1][2][3]11 Sajulga et al, identified low frequencies of rs1050458-G (arginine) and only one example of valine at P2 among over two million haplotypes. 11 Here we focused on validation of the rs1050458 dimorphism using empirical data from a next-generation sequencing (NGS) platform.…”

“…[1][2][3]11 Sajulga et al, identified low frequencies of rs1050458-G (arginine) and only one example of valine at P2 among over two million haplotypes. 11 Here we focused on validation of the rs1050458 dimorphism using empirical data from a next-generation sequencing (NGS) platform. We studied genotype frequencies of M-and T-leaders within a large cohort of patients and related and unrelated transplant donors.…”