AUTHOR=Suzuki Shingo , Morishima Satoko , Murata Makoto , Tanaka Masafumi , Shigenari Atsuko , Ito Sayaka , Kanga Uma , Kulski Jerzy K. , Morishima Yasuo , Shiina Takashi 

TITLE=Sequence Variations Within HLA-G and HLA-F Genomic Segments at the Human Leukocyte Antigen Telomeric End Associated With Acute Graft-Versus-Host Disease in Unrelated Bone Marrow Transplantation

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.938206

DOI=10.3389/fimmu.2022.938206

ISSN=1664-3224

ABSTRACT=<p>Acute graft-versus-host disease (aGVHD) is defined as a syndrome of an immunological response of graft to the host that occurs early after allogeneic hematopoietic stem cell transplantation (HCT). This disease is frequently observed even in HCT matched for human leukocyte antigen (HLA) alleles at multiple gene loci. Although the HLA region represents complex and diverse genomic characteristics, detailed association analysis is required for the identification of uncharacterized variants that are strongly associated with aGVHD. We genotyped three loci, <italic>OR2H2</italic>, <italic>HLA-F-AS1</italic>, and <italic>HLA-G</italic>, that are located in the 460 kb of HLA telomeric region and statistically analyzed the genotypes including <italic>HLA-DPB1</italic> with clinical and transplantation outcomes using 338 unrelated bone marrow transplantation (UR-BMT) patient–donor pairs who were matched for <italic>HLA-A</italic>, <italic>HLA-B</italic>, <italic>HLA-C</italic>, <italic>HLA-DRB1</italic>, and <italic>HLA-DQB1</italic> (HLA-10/10). Multivariate analyses demonstrated that <italic>HLA-F-AS1</italic> and <italic>HLA-DPB1</italic> mismatches were associated with grade II–IV aGVHD (hazard ratio (HR), 1.76; 95% CI, 1.07–2.88; p = 0.026; and HR, 1.59; CI, 1.02–2.49; p = 0.042, respectively). There was no confounding between <italic>HLA-F-AS1</italic> and <italic>HLA-DPB1</italic> (p = 0.512), suggesting that the <italic>HLA-F-AS1</italic> mismatch has a strong effect on aGVHD independently of <italic>HLA-DPB1</italic>. Moreover, a stratified analysis suggested possible associations of <italic>HLA-F-AS1</italic>, <italic>HLA-DPB1</italic>, and/or <italic>HLA-G</italic> mismatches with grade II–IV aGVHD and the more severe grade III–IV aGVHD. These findings provide new insights into understanding the molecular mechanism of aGVHD caused by HLA-matched UR-BMT.</p>