Hepatitis B viraemia: its heritability and association with common genetic variation in the interferon gamma signalling pathway

Objective High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon gamma (IFN gamma) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV. Methods We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFN gamma-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years. Results After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother-child pairs. Heritability accounted for approximately 30% (p < 0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFN gamma receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p < 0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of >= 4.39 log copies/ml (all p < 0.0001) in unrelated individuals. Conclusions HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.