Impact Of Candidate Genetic Polymorphisms On The Outcomes Of Hepatitis B Virus Infection

Backgroud and aims:Recently, genome-wide association studies (GWAS) have linked many single nucleotide polymorphisms (SNPs) with outcomes of liver diseases including hepatitis C, hepatitis B, nonalcoholic fatty liver disease and primary biliary cirrhosis. The identification of disease-related gene determinants would assist the prediction of individual risk of disease progression, understanding of pathophysiologic mechanisms of liver diseases, and providing personalized treatment strategy. Specifically, a fibrosis marker termed cirrhosis risk score (CRS) comprising of seven SNPs in seven genes has been proved able to identify liver cirrhosis in Caucasian hepatitis C patients. Seven genes including toll-like receptor 4 (TLR4), degenerative spermatocyte homolog 1, lipid desaturase (DEGS1), syntaxin-binding protein 5-like (STXBP5L), antizyme inhibitor 1 (AZIN1), transient receptor potential cation channel subfamily M, member 5 (TRPM5), adaptor-related protein complex 3, sigma 2 subunit (AP3S2) and aquaporin 2 (AQP2) have been identified as possible fibrosis-related genes. Additionally, multiple GWAS have powerfully demonstrated that rs 12979860 and rs8099917 in interleukin 28B (IL28B) gene on chromosome 19 which encodes interferon-lamda (IFN-?) 3 are associated with response to pegylated interferon-a and ribavirin therapy and natural clearance of hepatitis C. Patients of hepatitis C with the protective IL28B genotype had a much greater chance of achieving virological reponse and spontaneous viral clearance. The roles of the emerging SNPs are unclear in hepatitis B virus (HBV) infection which is another common entity of viral hepatitis. In the present study, the aim was mainly to evaluate whether the newly established SNPs were associated with development of chronic hepatitis, liver cirrhosis and persistence of infection in a Chinese population infected with HBV as few studies have been conducted to assess the value of the markers in hepatitis B patients. We also try to assess the clinical value of combination of multiple SNPs for identifying hepatits B phenotypes. Methods:A total of 988 Chinese participants with persistent HBV infection (429 with evident liver cirrhosis,285 without cirrhosis) and 274 healthy individuals who recovered from HBV infection, were studied. Occurrence of liver cirrhosis, liver cancer, disease progression, apparent hepatitis onset and HBV markers were determined. Genotypes of fourteen SNPs in nine candidate genes were detected with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The genotypic distributions of the SNPs were compared between HBV persisters with cirrhosis and HBV persisters without cirrhosis, and between HBV persisters and spontaneous clearance group, and also between other phenotypic pairs.Results:The population showed varied phenotypes of disease progression. The rs2679757 polymorphism of AZIN1 gene was associated with the risk of cirrhosis (odds ratio for GG+AG versus AA=1.47,95% confidence interval= 1.08-2.01, P=0.01). Rs886277 in TRPM5 gene was also associated with liver cirrhosis (odds ratio for CC versus CT+TT=1.63,95% confidence interval=1.20-2.22, P=0.002). The two SNPs also determined the overall severity of liver disease and disease progression rate. When combining both SNPs, the analysis produced a greater odds ratio (2.29,95% confidence interval 1.50-3.52) than that of any individual marker (P=0.000). In a subgroup of patients, the mean values of CRS were not different between the cirrhosis group and non-cirrhosis group (0.624 versus 0.636, P=0.511). Comparing the persistent infection group to the spontaneous clearance group, IL28B rs 12979860 CC genotype had a tendency of association with spontaneous clearance of hepatitis B surface antigen (odds ratio for CC versus CT+TT=0.61,95% confidence interval= 0.36-1.04, P=0.07). The two IL28B polymorphisms had no association with clearance of hepatitis B e antigen, HBV-DNA level, apparent hepatitis onset or liver cirrhosis. TLR4 rs4986791 and AZIN1 rs62522600 are not polymorphic in Chinese. Genotype frequencies of other SNPs were not different significantly between the cirrhosis and non-cirrhosis groups. No significant association was obtained for all SNPs in liver cancer analysis.Conclusions:This study provides additional confirmation of the importance of variation in genes and extends the European results to an East Asian population group. SNPs in AZINl, TRPM5 and IL28B genes may modulate risk of persistent infection and liver fibrosis of hepatitis B in Chinese. The emerging SNPs and associated genes warrant further clinical validation in hepatitis B patients and mechanistic investigation to reveal their roles in liver disease progression. Combination of multiple SNPs is a potentially advantageous fibrosis marker in chronic hepatitis.