Extended HLA Haplotypes and Transplant Survival

The benefit of extended HLA class I~class III~class II haplotypes in the reduction of mortality after hematopoietic-cell transplantation is unknown and requires information on functional class III variation. We identified a robust class III single-nucleotide-polymorphism (SNP), rs915654, informative for mortality and relapse in 1,436 patients and their haploidentical related donors through multivariable regression analysis of 26 candidate class III SNPs. Three-marker haplotypes as defined by one class I locus, one class II locus and rs915654 were determined in patients separately from donors. Inclusion of rs915654 into relapse and mortality models already containing patient HLA-E~DRB1 and donor HLA-B~DRB1 improved each model (likelihood ratio test P=0.06 and 0.004 respectively for relapse; P=0.10 and 0.01 respectively for mortality). The risks of mortality and relapse increased with decreasing numbers of favorable patient and donor markers. Re-testing in an independent cohort of 1,141 haploidentical transplants yielded similar results. The number of unfavorable markers additionally increased non-relapse mortality. HLA-A~C~B~DRB1~DQB1 haplotypes were defined according to their expected numbers of favorable markers, and the theoretical utility for selecting donors was explored. In summary, extended HLA class I~class III~class II haplotypes influence the success of transplantation and inform the biology of the MHC in health and disease. The selection of haploidentical donors for future patients may be optimized with knowledge of donor HLA haplotypes.