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Evolutionary basis of HLA-DPB1 alleles affects acute GVHD in unrelated donor stem cell transplantation

Satoko Morishima, Takashi Shiina, Shingo Suzuki, Seishi Ogawa, Aiko Sato-Otsubo, Koichi Kashiwase, Fumihiro Azuma, Toshio Yabe, Masahiro Satake, Shunichi Kato, Yoshihisa Kodera, Takehiko Sasazuki and Yasuo Morishima

Key points

  • HLA-DPB1 alleles diverged into two major groups according to highly conserved DNA sequences from exon 3 to 3'UTR.

  • Two evolutionarily different HLA-DPB1 gene regions complementarily affect acute GVHD in HLA-DPB1 mismatch UR-HCT.

Abstract

HLA-DPB1 T-cell epitope (TCE) mismatching algorithm and rs9277534 SNP at the 3′ untranslated region (3′ UTR) in the HLA-DPB1 gene are key factors for transplant-related events in unrelated hematopoietic cell transplantation (UR-HCT). However, the association of these two mechanisms has not been elucidated. We analyzed 19 frequent HLA-DPB1 alleles derived from Japanese healthy subjects by next-generation sequencing (NGS) of the entire HLA-DPB1 gene region and multi-SNP data of the HLA region in 1589 UR-HCT pairs. The risk of acute graft-versus-host disease (aGVHD) was analyzed in 1286 patients with single HLA-DPB1 mismatch UR-HCT. The phylogenetic tree constructed using the entire gene region demonstrated that HLA-DPB1 alleles were divided into two groups, HLA-DP2 and -DP5. Although a phylogenetic relationship in the genomic region from exon 3 to 3′UTR (Ex3-3′UTR) obviously supported the division of HLA-DP2- and -DP5-groups, that in exon 2 showed intermingling of HLA-DPB1 alleles in a non-HLA-DP2- and -DP5-group manner. Multi-SNP data also showed two discriminative HLA-DPB1 groups according to Ex3-3′UTR. Risk of grade II-IV aGVHD was significantly higher in patient HLA-DP5-group mismatch than patient HLA-DP2-group mismatch (HR, 1.28; P=0.005), regardless of donor mismatch HLA-DP-group. Regarding TCE mismatch, increasing risk of aGVHD in patient HLA-DP5-group mismatch and TCE-non-permissive-mismatch were observed only in patients with TCE-permissive-mismatch and patient HLA-DP2-group mismatch, respectively. Evolutionary analysis revealed that rs9277534 represented a highly conserved HLA-DPB1 Ex3-3′UTR region, and may provoke aGVHD differently to TCE mismatching algorithm, reflecting exon 2 polymorphisms. These findings enrich our understanding of the mechanism of aGVHD in HLA-DPB1 mismatch UR-HCT.

  • Submitted August 14, 2017.
  • Accepted December 3, 2017.