Mendelian randomization study on the causal relationship between chronic hepatitis B/C virus infection and idiopathic pulmonary fibrosis.

Background: The pathogenesis of idiopathic pulmonary fibrosis (IPF) is not well understood. Given the known role of hepatitis C virus (HCV) in inducing cirrhosis, the virus has also received attention in the study of IPF. An earlier retrospective study found an increased incidence of IPF in patients with HCV, supported by evidence in the alveolar lavage fluid of the patients, whereas another set of observational studies did not find an association, which prompted us to explore a causal relationship. It is well known that HCV and hepatitis B virus (HBV) have some similarities: both are RNA viruses, and both have a strong ability to induce cirrhosis, which in turn leads to poor prognosis and increased mortality in patients with viral hepatitis. This factor also inspired us to start exploring whether there is a causal relationship between HBV and IPF. Due to the inherent limitations of previous studies, causality between chronic HBV/HCV infection and IPF is yet to be established. Mendelian randomization (MR) uses genetic variation as exposure and can be used to determine the causal effect of exposure on outcomes. Therefore, we used a two-sample MR study to determine if there is a causal relationship between viral hepatitis and IPF risk.

Methods: Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs), with chronic HBV and HCV infections as exposure factors and IPF as the outcome variable. Three methods, inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression, were employed for the bidirectional MR. Sensitivity analyses, including horizontal pleiotropy analysis, Cochran's Q test, and leave-one-out evaluation of result reliability, were conducted. Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and MR-Egger regression tests were used to monitor potential horizontal pleiotropic effects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to interpret the causal relationship between chronic HBV and HCV infections and IPF. Finally, reverse MR analysis was performed to validate the robustness of the results.

Results: The results of the IVW suggested that there was no causal relationship between chronic HBV infection (OR =1.039, 95% CI: 0.935-1.154, P=0.48) and chronic HCV infection (OR =1.146, 95% CI: 0.834-1.576, P=0.40) and the risk of IPF. Sensitivity analysis showed no evidence of reverse causation, horizontal pleiotropy, and heterogeneity.

Conclusions: This study, using the bidirectional MR, provides preliminary evidence that chronic HBV and HCV infections are not causally related to IPF at the genetic level. However, this conclusion requires support from larger sample sizes in genome-wide association study (GWAS) databases for further MR analysis, and additional clinical studies and animal experiments are needed for validation.