Abstract
HLA matching is a critical factor for successful allogeneic hematopoietic stem cell transplantation. For unrelated donor searches, matching is usually based on high-resolution typing at five HLA loci, looking for a 10/10 match. Some studies have proposed that further matching at the haplotype level could be beneficial for clinical outcome. In this study, we determined the phased haplotypes of 291 patients using family members and segregation analysis. The sum of ranks of the haplotypes carried by patients was used as a surrogate predictor of a successful unrelated donor search. The putative impact of haplotypes was then analyzed in a cohort of 211 recipients transplanted with 10/10 matched unrelated donors. A logistic regression analysis showed a highly significant effect of the haplotypes in the outcome of a search, but we did not find any significant effect on overall survival, graft versus host disease or relapse/progression following HSCT. This study provides useful data for the optimization of unrelated bone marrow donor searches, but does not confirm previous reports that matching at the haplotype level has a clinical impact following HSCT. Due to the extreme polymorphism of HLA genes, further studies are warranted to better understand the many factors at play.
Highlights
Human leukocyte antigen (HLA) matching between recipients and donors is a prerequisite for successful allogeneic hematopoietic stem cell transplantation (HSCT), notably to Supplementary information The online version of this article contains supplementary material, which is available to authorized users.no consideration given to putative haplotype matching between the recipient and his donor
A total of 420 distinct high-resolution HLA-A~B~DRB1 haplotypes were phased by segregation analysis in the 291 patients and HW equilibrium was not rejected at any locus
The three loci were not significantly associated to each other (p-value of 1 according to the likelihood-ratio test, no extreme value according to parametric resampling for global linkage disequilibrium)
Summary
Even with well-matched unrelated donors, risks of transplant-related mortality are higher as compared to matched sibling donors because of minor histocompatibility antigens (mHA) spread across the whole genome and non-HLA linked polymorphisms (e.g. single nucleotide polymorphisms (SNPs), expression quantitative trait loci (eQTL), microsatellites) within the extended HLA region [6,7,8,9,10,11,12]. HLA haplotypes can either be phased unambiguously by family segregation analysis or imputed statistically from genotype data and HLA frequencies in populations. The underlying hypothesis is that if a recipient and his unrelated donor are matched for the same common haplotypes, such haplotypes could carry more conserved DNA segments shared by descent (including at nearby favorable SNPs) compared to rare haplotypes present in the population
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