Hepatitis B infection is causally associated with extrahepatic cancers: A Mendelian randomization study

Background: Evidence from observational studies suggests that chronic hepatitis B virus (HBV) infection is associated with extrahepatic cancers. However, the causal association between chronic HBV infection and extrahepatic cancers remains to be determined. Methods: We performed two-sample Mendelian randomization (MR) to investigate whether chronic HBV infection is causally associated with extrahepatic cancers. We identified four independent genetic variants strongly associated (P-value < 5 × 10−8) with the exposure, chronic HBV infection in 1371 cases and 2938 controls of East Asian ancestry in Korea, which were used as instrumental variables. Genome-wide association summary level data for outcome variables, that included cancer of the biliary tract, cervix, colorectum, endometrium, esophagus, gastric, hepatocellular carcinoma, lung, ovary and pancreas were obtained from Biobank Japan. Findings: Using the multivariable inverse variance weighted method, we found genetic liability to chronic HBV infection causally associated with extrahepatic cancers including cervical cancer (odds ratio [OR] = 1.57, 95% confidence interval [CI] = 1.29–1.91, P-value = 0.0001) and gastric cancer (OR = 1.12, 95% CI = 1.05–1.19, P-value = 0.0001). Moreover, chronic HBV infection (OR = 1.20, 95% CI = 1.07–1.34, P-value = 0.0021) was causally associated with hepatocellular carcinoma, supporting a well-established association between chronic HBV infection and hepatocellular carcinoma. Interpretation:: Our MR analysis revealed that chronic HBV infection is causally associated with extrahepatic cancers including cervical and gastric cancers. Funding: None.