Feng Zepei, Huang Peng, Zhang Jinwei, Xia Xueshan, Zhang A-Mei, Zeng Tian, Chen Qiong, Zhu Chuanlong, Tan Weilong, Zhang Yun, Yue Ming
Department of Epidemiology and Biostatistics, Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing, China.
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
J Med Virol. 2023 Mar;95(3):e28645. doi: 10.1002/jmv.28645.
Killer-cell immunoglobulin-like receptors 2DL4 (KIR2DL4) and the human leukocyte antigen class I-G (HLA-G) display vital parts in immune responses against hepatitis C virus (HCV) infection. We select four potentially functional single nucleotide polymorphisms (SNPs) of KIR/HLA to explore the associations between KIR2DL4/HLA-G genetic variants and HCV infection results. In the present case-control study, a total of 2225 HCV-infected high-risk subjects, including 1778 paid blood donors (PBD) and 447 drug users were consecutively recruited before treatment from 2011 to 2018. KIR2DL4-rs660773, KIR2DL4-rs660437, HLA-G-rs9380142, and HLA-G-rs1707 SNPs were sorted as genotypes in the subdivided groups, involving 1095 uninfected controls subjects, 432 spontaneous HCV clearance subjects and 698 HCV persistent infection subjects. After genotyping experiments using the TaqMan-MGB assay, modified logistic regression was used to calculate the correlation among the SNPs and HCV infection. The SNPs were functionally annotated using bioinformatics analysis. Following adjusting by age, sex, alanine aminotransferase, aspartate aminotransferase, IFNL3-rs12979860, IFNL3-rs8099917, and the infection route, the logistic regression analysis discovered that KIR2DL4-rs660773 and HLA-G-rs9380142 were correlated with vulnerability to HCV infection (all p < 0.05). In a locus-dosage way, compared with subjects carrying the rs9380142-AA or rs660773-AA genotypes, subjects with rs9380142-AG or rs660773-AG/GG (all p < 0.05) were more vulnerable to HCV infection; the overall impact of their risk genotypes (rs9380142-AGrs660773-AG/GG) was correlated with an elevated incidence of HCV infection (p < 0.001). In the Haplotype analysis, patients with haplotype AG were more likely to contract HCV compared to those with the highest common AA haplotype (p = 0.002) were higher in susceptibility to infect HCV. The SNPinfo web server estimated that rs660773 is a transcription factor binding site, whereas rs9380142 is a potential microRNA-binding site. In two Chinese high-risk population (PBD and drug uesrs), KIR2DL4 rs660773-G and HLA-G rs9380142-G alleles polymorphisms are related to HCV susceptibility. KIR2DL4/HLA-G pathway genes might affect the innate immune responses by regulating KIR2DL4/HLA-G transcription and translation play a potential role in HCV infection.
杀伤细胞免疫球蛋白样受体2DL4（KIR2DL4）和人类白细胞抗原I类G（HLA - G）在丙型肝炎病毒（HCV）感染的免疫反应中发挥着重要作用。我们选择了KIR/HLA的四个潜在功能性单核苷酸多态性（SNP），以探讨KIR2DL4/HLA - G基因变异与HCV感染结果之间的关联。在本病例对照研究中，2011年至2018年期间，共连续招募了2225名HCV感染高危受试者，包括1778名有偿献血者（PBD）和447名吸毒者，均在治疗前纳入。将KIR2DL4 - rs660773、KIR2DL4 - rs660437、HLA - G - rs9380142和HLA - G - rs1707 SNPs按基因型分类到亚组中，涉及1095名未感染对照受试者、432名HCV自发清除受试者和698名HCV持续感染受试者。使用TaqMan - MGB分析进行基因分型实验后，采用修正的逻辑回归分析来计算SNP与HCV感染之间的相关性。通过生物信息学分析对SNP进行功能注释。在对年龄、性别、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、IFNL3 - rs12979860、IFNL3 - rs8099917和感染途径进行校正后，逻辑回归分析发现KIR2DL4 - rs660773和HLA - G - rs9380142与HCV感染易感性相关（所有p < 0.05）。以基因座剂量方式分析，与携带rs9380142 - AA或rs660773 - AA基因型的受试者相比，携带rs9380142 - AG或rs660773 - AG/GG基因型的受试者更易感染HCV（所有p < 0.05）；其风险基因型（rs9380142 - AG rs660773 - AG/GG）的总体影响与HCV感染发生率升高相关（p < 0.001）。在单倍型分析中，与具有最常见的AA单倍型的患者相比，具有AG单倍型的患者感染HCV的可能性更高（p = 0.002），对HCV感染的易感性更高。SNPinfo网络服务器估计rs660773是一个转录因子结合位点，而rs9380142是一个潜在的微小RNA结合位点。在两个中国高危人群（PBD和吸毒者）中，KIR2DL4 rs660773 - G和HLA - G rs9380142 - G等位基因多态性与HCV易感性相关。KIR2DL4/HLA - G通路基因可能通过调节KIR2DL4/HLA - G的转录和翻译影响先天免疫反应，在HCV感染中发挥潜在作用。
