Impact of highly conserved HLA haplotype on acute graft-versus-host disease

Although the effects of human leukocyte antigen (HLA) locus matching on clinical outcome in unrelated hematopoietic stem cell transplantations have been characterized, the biologic implications of HLA haplotypes have not been defined. We demonstrated the genetic fixity of Japanese conserved extended haplotypes by multi-single nucleotide polymorphism analysis in 1810 Japanese donor-recipient pairs matching with HLA-A, -B, -C, -DRB1, and -DQB1 alleles. Three major Japanese conserved extended haplotypes (named HP-P1, HP-P2, and HP-P3) were essentially completely conserved at least in the 3.3-Mb HLA region from HLA-A to -DPB1, and extended far beyond HLA-A. The risk of acute graft-versus-host disease (GVHD) of these HLA haplotypes was assessed with multivariate Cox regression in 712 patients transplanted from HLA fully (HLA-A, B, C, DRB1, DQB1, and DPB1) matched unrelated donors. HP-P2 itself reduced the risk of grade 2 to 4 acute GVHD (hazard ratio [HR] = 0.63; P = .032 compared with HP-P2-negative), whereas HP-P3 tended to increase the risk (HR = 1.38; P = .07). Among 381 patients with HP-P1, HP-P1/P3 (HR = 3.35; P = .024) significantly increased the risk of acute GVHD compared with homozygous HP-P1. This study is the first to demonstrate that a genetic difference derived from HLA haplotype itself is associated with acute GVHD in allogeneic hematopoietic stem cell transplantation.