Causal role of 46 pathogen-derived antibodies in prostate disease insights from two-sample and Bayesian-weighted Mendelian randomization.

[BACKGROUND] Prostate diseases, including prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa), are common in men and involve complex pathogenesis. Increasing evidence suggests that pathogen infections may influence prostate disease development through immune activation and chronic inflammation. However, causal relationships remain unclear.

[METHODS] We conducted two-sample Mendelian randomization (MR) and Bayesian weighted MR (BWMR) analyses to investigate the causal association between pathogen-specific antibody levels and prostate disease risk. Genetic data for pathogen antibodies were obtained from the UK Biobank, and GWAS summary statistics for prostatitis, BPH, and PCa were sourced from large public databases. Multiple sensitivity analyses were performed to validate the robustness of the findings.

[RESULTS] Positive levels of herpes simplex virus-2 (HSV-2) mgG-1, Epstein-Barr virus (EBV) EBNA-1, and human herpesvirus-6 (HHV-6) IE1B antibodies were associated with an increased risk of prostatitis, whereas EBV ZEBRA and HHV-7 U14 antibodies were protective. For PCa, HHV-6 E1A antibodies were risk factors, while HHV-7 IgG and Helicobacter pylori VacA antibodies exhibited protective effects. In BPH, EBV VCA p18, HSV-2 IgG, and Helicobacter pylori IgG antibodies increased risk, whereas Helicobacter pylori peroxidase, OMP, and EBV ZEBRA antibodies showed protective associations. No evidence of reverse causality was found.

[CONCLUSION] This study provides genetic evidence supporting a potential causal role of specific pathogen infections in the development of prostate diseases. Targeted prevention of certain infections may contribute to reducing prostate disease risk. Future studies are warranted to validate these findings across diverse populations and to elucidate the underlying biological mechanisms.