Mendelian randomization reveals no correlations between herpesvirus infection and idiopathic pulmonary fibrosis

BACKGROUND: Previous studies have found that the persistence of herpesvirus significantly increases the risk of idiopathic pulmonary fibrosis (IPF), but it is unclear whether this effect is causal. We conducted a two-sample Mendelian randomization (MR) study to evaluate the causal relationship between three herpesvirus infections and IPF. METHODS: We used genome-wide association studies (GWAS) data from three independent datasets, including FinnGen cohort, Milieu Intérieur cohort, and 23andMe cohort, to screen for instrumental variables (IVs) of herpesvirus infection or herpesvirus-related immunoglobulin G (IgG) levels. Outcome dataset came from the largest meta-analysis of IPF susceptibility currently available. RESULTS: In the FinnGen cohort, genetically predicted Epstein-Barr virus (EBV) (OR = 1.105, 95%CI: 0.897–1.149, p = 0.815), cytomegalovirus (CMV) (OR = 1.073, 95%CI: 0.926–1.244, p = 0.302) and herpes simplex (HSV) infection (OR = 0.906, 95%CI: 0.753–1.097, p = 0.298) were not associated with the risk of IPF. In the Milieu Intérieur cohort, we found no correlations between herpesvirus-related IgG EBV nuclear antigen-1 (EBNA1) (OR = 0.968, 95%CI: 0.782–1.198, p = 0.764), EBV viral capsid antigen (VCA) (OR = 1.061, 95CI%: 0.811–1.387, p = 0.665), CMV (OR = 1.108, 95CI%: 0.944–1.314, p = 0.240), HSV-1 (OR = 1.154, 95%CI: 0.684–1.945, p = 0.592) and HSV-2 (OR = 0.915, 95%CI: 0.793–1.056, p = 0.225) and IPF risk. Moreover, in the 23andMe cohort, no evidence of associations between mononucleosis (OR = 1.042, 95%CI: 0.709–1.532, p = 0.832) and cold scores (OR = 0.906, 95%CI: 0.603–1.362, p = 0.635) and IPF were found. Sensitivity analysis confirmed the robustness of our results. CONCLUSIONS: This study provides preliminary evidence that EBV, CMV, and HSV herpesviruses, and herpesviruses-related IgG levels, are not causally linked to IPF. Further MR analysis will be necessary when stronger instrument variables and GWAS with larger sample sizes become available.