Mendelian randomization unveils genetic causal relationships between viral infections and systemic sclerosis

Abstract

This study uses Mendelian randomization (MR) to investigate the potential causal relationships between viral infections, including Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), SARS-CoV-2, cytomegalovirus (CMV), human herpes virus 6 (HHV-6), varicella-zoster virus (VZV), herpes simplex virus (HSV), influenza A virus, and hepatitis B virus, and the risk of systemic sclerosis (SSc). Summary-level data on viral exposures and SSc outcomes were obtained from public genome-wide association studies (GWAS) databases. Causality was assessed using the inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Sensitivity analysis was conducted to enhance the reliability and robustness of our findings. Genetically predicted anti-EBV viral capsid antigen IgG levels (OR = 3.400, 95% CI = 1.093–10.571, p = 0.035) were causally associated with an elevated risk of SSc, while HIV (OR = 0.787, 95% CI = 0.629–0.985, p = 0.037) and SARS-CoV-2 (OR = 0.335, 95% CI = 0.116–0.964, p = 0.043) correlated with a reduced risk of SSc. Sensitivity analysis validated the robustness of these associations (p > 0.05). Further elucidation of the underlying mechanisms by which EBV increases the risk of SSc could potentially identify interventions for promoting SSc prevention.