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

• Published in: Blood Vol. 131; no. 7; pp. 808 - 817
• Main Authors: Morishima, Satoko, Shiina, Takashi, Suzuki, Shingo, Ogawa, Seishi, Sato-Otsubo, Aiko, Kashiwase, Koichi, Azuma, Fumihiro, Yabe, Toshio, Satake, Masahiro, Kato, Shunichi, Kodera, Yoshihisa, Sasazuki, Takehiko, Morishima, Yasuo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2018; American Society of Hematology
• Subjects: Acute Disease; Adolescent; Adult; Aged; Alleles; Child; Child, Preschool; Evolution, Molecular; Female; Genetic Predisposition to Disease; Graft vs Host Disease - genetics; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; HLA-DP beta-Chains - genetics; Humans; Infant; Infant, Newborn; Male; Middle Aged; Phylogeny; Polymorphism, Genetic; Transplantation; Unrelated Donors; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2017-08-801449

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 2 mechanisms has not been elucidated. We analyzed 19 frequent HLA-DPB1 alleles derived from Japanese healthy subjects by next-generation sequencing 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 2 groups, HLA-DP2 and HLA-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 HLA-DP5 groups, which in exon 2 showed intermingling of HLA-DPB1 alleles in a non–HLA-DP2 and non–HLA-DP5-group manner. Multi-SNP data also showed 2 discriminative HLA-DPB1 groups according to Ex3-3′UTR. Risk of grade 2-4 aGVHD was significantly higher in patient HLA-DP5 group mismatch than patient HLA-DP2 group mismatch (hazard ratio, 1.28; P = .005), regardless of donor mismatch HLA-DP group. Regarding TCE mismatch, increasing risk of aGVHD in patient HLA-DP5 group mismatch and TCE-nonpermissive 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. •HLA-DPB1 alleles diverged into 2 major groups according to highly conserved DNA sequences Ex3-3′UTR.•Two evolutionarily different HLA-DPB1 gene regions complementarily affect aGVHD in HLA-DPB1 mismatch UR-HCT.