Cancer risk associated with hepatic viral infection and genetic susceptibility of HBV infection

ABSTRACT
Background and Aim: Hepatitis is a viral infection that causes liver inflammation and damage, posing a significant threat to human health. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major contributors to chronic liver disease, cirrhosis, and hepatocellular carcinoma in Taiwan and around the world. Numerous studies have highlighted significant associations between HBV/HCV infection and both hepatic and extra-hepatic cancers. However, inadequacies in confounder control, particularly lifestyle behaviors, environmental factors, and genetic risks, persist in hospital-based databases. Our first objective was to examine the relationship between hepatic viral infections and the risk of various cancer types in Taiwan, considering risk factors unique to each cancer type. Our second objective was to conduct comprehensive genome-wide association studies (GWAS) to identify single nucleotide polymorphisms (SNPs) linked to HBV infectivity and viral mutation.
Materials and Methods: This research was implemented in two phases. In the first phase, a cross-sectional study was conducted using a Taiwan Biobank (TWB) dataset. The exposure group included individuals seropositive for HBV or HCV, while the control group constituted individuals with negative HBV or HCV diagnosis. The outcomes of interest included the most commonly diagnosed cancers among the Taiwanese population, monitored from the initial enrollment period through the end of 2021. Logistic regression was employed to estimate the odds ratios (ORs) along with their corresponding 95% confidence intervals (CIs) for cancers associated with viral hepatitis. A sensitivity analyses was conducted where the dual infection group was excluded. In the second phase, GWAS were used to scrutinize genetic variants associated with HBV infectivity and viral mutation, using data from the Taiwan Biobank. Five phenotype groups were defined based on three HBV biomarkers: hepatitis B surface antigen (HBsAg), antibodies to Hepatitis B core antigen (anti-HBc), and antibodies to hepatitis B surface antigen (anti-HBs). Comparisons 1 - 3 focused on HBV infectivity, while comparisons 4 and 5 addressed viral mutation. An additive model was used to estimate ORs for SNP associations, adjusting for significant principal components and covariates.
Results: The study identified 2,955 individuals with HCV infection, 15,305 with HBV infection, while 140,108 participants categorized as non-viral cases. The findings showed a significant association between HBV infection and an increased risk of liver cancer (adjusted odds ratio [aOR] = 6.60, 95% CI = 3.21-13.57, P < 0.001) as well as ovarian cancer (aOR = 4.63, 95% CI: 1.98-10.83, P = 0.001). Similarly, there was association of HCV infection with an elevated risk of liver cancer (aOR = 4.90, 95% CI: 1.37-17.53, P = 0.015), kidney cancer (aOR = 12.89, 95% CI: 2.41-69.01, P = 0.003), and ovarian cancer (aOR = 8.50, 95% CI: 1.78-40.69, P = 0.007). In the second phase of our study, we identified six independent loci associated with HBV infection status after clumping 500KB around the lead SNPs. Of the independent loci, rs2296651 (SLC10A1) was associated with HBV susceptibility, vaccination or immunity. The rs9275373 (HLA-DQB1) was associated with HBV vaccination or immunity, whereas rs7770501 (HLA-DPB1), rs9268926 (HLA-DRB5), and rs12614 (CFB) were associated with previous HBV infection. We also found that rs140075738 (C11orf73) was associated with the HBV mutation status. Our fine mapping around the independent loci identified two SNPs (rs2844458 and rs2858302) with a posterior probability of causality (PP) of 99% in a single credible set size driving the association.
Conclusion: This study demonstrates that both HBV and HCV infections are significantly associated with increased risks of liver, ovarian, and kidney cancers. Additionally, several genetic loci were identified that influence susceptibility to HBV infection and viral mutation. These findings enhance our understanding of the links between viral hepatitis, cancer risk, and host genetics, providing valuable insights for future prevention and intervention strategies.