DataSheet_6_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.pdf

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, OR2H2, HLA-F-AS1, and HLA-G, that are located in the 460 kb of HLA telomeric region and statistically analyzed the genotypes including HLA-DPB1 with clinical and transplantation outcomes using 338 unrelated bone marrow transplantation (UR-BMT) patient–donor pairs who were matched for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 (HLA-10/10). Multivariate analyses demonstrated that HLA-F-AS1 and HLA-DPB1 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 HLA-F-AS1 and HLA-DPB1 (p = 0.512), suggesting that the HLA-F-AS1 mismatch has a strong effect on aGVHD independently of HLA-DPB1. Moreover, a stratified analysis suggested possible associations of HLA-F-AS1, HLA-DPB1, and/or HLA-G 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.

急性移植物抗宿主病（acute graft-versus-host disease, aGVHD）被定义为异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation, HCT）后早期发生的移植物抗宿主免疫应答综合征。即便在多基因位点人类白细胞抗原（human leukocyte antigen, HLA）等位基因匹配的造血干细胞移植中，该病也较为高发。尽管HLA区域具有复杂多样的基因组特征，仍需开展精细化关联分析以鉴定出与aGVHD强相关的未表征变异位点。本研究对位于HLA端粒区域460kb范围内的OR2H2、HLA-F-AS1及HLA-G三个基因位点进行了基因分型，并针对338对HLA-A、HLA-B、HLA-C、HLA-DRB1及HLA-DQB1全匹配（HLA-10/10）的无关供体骨髓移植（unrelated bone marrow transplantation, UR-BMT）供者-患者对，结合临床与移植结局，对包括HLA-DPB1在内的基因型开展了统计学分析。多变量分析结果显示，HLA-F-AS1与HLA-DPB1错配均与Ⅱ~Ⅳ级aGVHD显著相关（风险比（hazard ratio, HR）分别为1.76、1.59；95%置信区间（95% CI）分别为1.07~2.88、1.02~2.49；P值分别为0.026、0.042）。HLA-F-AS1与HLA-DPB1之间不存在混杂效应（P=0.512），提示HLA-F-AS1错配可独立于HLA-DPB1对aGVHD产生显著影响。此外，分层分析结果提示，HLA-F-AS1、HLA-DPB1及/或HLA-G错配可能与Ⅱ~Ⅳ级aGVHD以及更严重的Ⅲ~Ⅳ级aGVHD存在关联。本研究结果为理解HLA匹配的无关供体骨髓移植所致aGVHD的分子机制提供了全新见解。