Utilizing bidirectional Mendelian randomization to uncover the relationship between infectious diseases and primary biliary cholangitis
TL;DR
EBNA-1 antibodies potentially exerting a protective effect and ZEBRA antibodies acting as a risk factor plays a dual role in the pathogenesis of PBC, highlighting the complex host–pathogen interactions that require further in-depth study.
Abstract
Aims: To explore the causal relationship between infectious disease pathogen antibodies and primary biliary cholangitis (PBC) using bidirectional Mendelian randomization (MR) and verify whether PBC has a reverse causal effect on the body’s antibody response to infectious pathogens, thereby providing new insights into PBC’s etiology and a theoretical basis for its prevention and treatment. Methods: Using Mendelian randomization (MR), we analyzed 46 antibodies against 13 infectious agents (exposures) and PBC (outcome), with single nucleotide polymorphisms (SNPs) from Butler-Laporte et al. as instrumental variables; PBC genome-wide association study (GWAS) data were obtained from FinnGen. Generalized summary-data-based Mendelian randomization (GSMR), inverse variance-weighted (IVW), and multiple sensitivity analyses were performed, with statistical significance set at Bonferroni-corrected P greater 5.43 × 10−4, and a False Discovery Rate (FDR) approach was also applied. Results: Epstein–Barr virus (EBV) EBNA-1 antibodies reduced the risk of PBC (OR [odds ratio] = 0.552, P = 1.002 × 10−6), while EBV ZEBRA antibodies increased PBC risk (OR = 1.646, P = 7.239 × 10−5). Nominally significant associations were observed for anti-Merkel cell polyomavirus immunoglobulin G (IgG) (OR = 1.322, P = 5.759 × 10−4), anti-herpes simplex virus 2 IgG (OR = 1.234, P = 0.029), and Chlamydia trachomatis momp A antibodies (OR = 1.110, P = 0.033) with PBC risk. Reverse MR analysis indicated that PBC may lower the levels of EBV viral capsid antigen (VCA) p18 (OR = 0.960, P = 0.004) and EBNA-1 (OR = 0.966, P = 0.017) antibodies, while potentially increasing others such as human herpesvirus 6 (HHV-6) and Helicobacter pylori. Conclusion: Epstein–Barr virus plays a dual role in the pathogenesis of PBC, with EBNA-1 antibodies potentially exerting a protective effect and ZEBRA antibodies acting as a risk factor. Other pathogenic microorganisms may also contribute to PBC development, highlighting the complex host–pathogen interactions that require further in-depth study.