Impacts of human leukocyte antigen DQ genetic polymorphisms and their interactions with hepatitis B virus mutations on the risks of viral persistence, liver cirrhosis, and hepatocellular carcinoma

Human leukocyte antigen (HLA)-DQ genetic polymorphisms have been associated with chronic hepatitis B virus (HBV) outcomes. We aimed to determine impacts of HLA-DQ polymorphisms and their interactions with HBV mutations on the risks of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). rs2856718 (A > G) and rs9275319 (A > G) were genotyped in 1342 healthy controls, 327 HBV surface antigen (HBsAg) seroclearance subjects, 611 asymptomatic HBsAg carriers (ASCs), 1144 chronic hepatitis B (CHB) patients, 734 LC patients, and 1531 HCC patients using quantitative PCR. HBV mutations were detected by direct sequencing. Logistic regression analyses were utilized to assess the factors and/or multiplicative interactions significantly associated with liver diseases. rs9275319 variant genotypes were inversely associated with HBV persistence compared to HBV natural clearance subjects. rs2856718 variant genotypes significantly increased LC risk compared to ASCs plus CHB patients (GG vs. AA: odds ratio [OR], 1.52, 95% confidence interval [CI], 1.17-1.97 and AG + GG vs. AA: OR, 1.27; 95% CI, 1.04-1.54) and decreased HCC risk compared to HCC-free HBV-infected subjects (AG vs. AA: OR, 0.76; 95% CI, 0.65-0.89 and AG + GG vs. AA: OR, 0.78, 95% CI, 0.68-0.90). rs2856718 variant genotypes were significantly associated with an increased frequency of HBV A1726C mutation, a LC-risk, HCC-protective mutation, in genotype C. A rs9275319 variant genotype (GG) was significantly associated with an increased frequency of preS1 start codon mutation, an HCC-risk mutation, in genotype C. The interaction of rs2856718 AG + GG genotype with T1753V, a HCC-risk mutation, significantly reduced LC risk, with an OR of 0.26 (95% CI, 0.09-0.78); whereas the interaction of rs2856718 AG genotype with C1673T, a LC-risk mutation, significantly increased HCC risk, with an OR of 2.80 (95% CI, 1.02-7.66) in genotype C HBV-infected subjects. Conclusively, the HLA-DQ polymorphisms affect the risks of LC and HCC differently in chronic HBV-infected subjects, possibly via interacting with the HBV mutations.