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Research Article
Utilizing bidirectional Mendelian randomization to uncover the relationship between infectious diseases and primary biliary cholangitis
1 General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
2 Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
Address correspondence to:
Lei Zhou
General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui
†These authors contributed equally to this work and share first authorship.,
China
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Article ID: 100112Z04YY2026
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Yang Y, Zhao Z, Huo J, Guo K, Zhou L. Utilizing bidirectional Mendelian randomization to uncover the relationship between infectious diseases and primary biliary cholangitis. Int J Hepatobiliary Pancreat Dis 2026;15(2):14–21.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 < 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.
Keywords: Causal relationship, Host–pathogen interaction, Infectious disease, Mendelian randomization, Primary biliary cholangitis
SUPPORTING INFORMATION
Acknowledgments
We express our gratitude to UK Biobank and FinnGen biobank for publicly sharing their datasets, and we sincerely thank all the researchers and participants involved in these studies. This study was supported by Natural Science Youth Project of Bengbu Medical University (No. 2024byzd085) and the 2024 Science and Technology Innovation Guidance Program of Bengbu City (No.18).
Artificial intelligence (AI) use in the article:
• No generative AI technology was used in the preparation of this manuscript, and no AI tool is listed as a co-author.
• No content generated by AI was included in any section of the article.
Yunchuan Yang † - Substantial contributions to conception and design, Interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Zhengxin Zhao † - Substantial contributions to conception and design, Acquisition of data, Analysis of data, Interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Junyi Huo - Substantial contributions to conception and design, Acquisition of data, Analysis of data, Interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Ke Guo - Interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Lei Zhou - Interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of SubmissionThe corresponding author is the guarantor of submission.
Source of SupportNone
Consent StatementWritten informed consent was obtained from the patient for publication of this article.
Data AvailabilityAll relevant data are within the paper and its Supporting Information files.
Conflict of InterestAuthors declare no conflict of interest.
Copyright© 2026 Yunchuan Yang et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.
