Genetic link between rheumatoid arthritis and autoimmune liver diseases: A two-sample Mendelian randomization study

Junyu Fan; Ting Jiang; Dongyi He

doi:10.1016/j.semarthrit.2022.152142

Genetic link between rheumatoid arthritis and autoimmune liver diseases: A two-sample Mendelian randomization study

Semin Arthritis Rheum. 2023 Feb:58:152142. doi: 10.1016/j.semarthrit.2022.152142. Epub 2022 Nov 24.

Authors

Junyu Fan¹, Ting Jiang¹, Dongyi He²

Affiliations

¹ Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China; Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai 200052, China.
² Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China; Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai 200052, China; Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200052, China. Electronic address: hedongyi1967@shutcm.edu.cn.

PMID: 36446255
DOI: 10.1016/j.semarthrit.2022.152142

Abstract

Background: An association between rheumatoid arthritis (RA) and autoimmune liver diseases (AILDs) was found in observational studies. However, neither the direction nor the cause-effect chain was clear. This study aimed to assess the causal associations between AILDs and RA.

Methods: We performed a two-sample Mendelian randomization (MR) analysis. Following a strict assessment, genome-wide association study (GWAS) datasets were used to select potential candidate single-nucleotide polymorphisms. The inverse-variance weighted (IVW) was used as the primary analysis approach, supplemented with four sensitive analysis methods applied to assess the robustness of the results.

Results: We discovered that a genetically increased primary biliary cholangitis (PBC) risk had a positive causal effect on RA (IVW OR=1.149, 95% CI=1.063-1.241, P<0.001). According to the MR-Egger regression, horizontal pleiotropy was unlikely to impact causality (intercept = -0.028, P = 0.263). Using the leave-one-out strategy, sensitivity studies revealed that the MR analysis results were robust and reliable. Genetically determined primary sclerosing cholangitis (PSC) was not linked with the risk of RA (IVW OR=1.071, 95%CI=0.984-1.166, P = 0.111). The results of the MR analysis were further validated by sensitivity analyses utilizing the leave-one-out approach. In the other direction, there was no causal relationship between RA and PBC (OR=1.132, 95% CI=0.881-1.454, P = 0.333) or PSC (OR=1.067, 95% CI=0.891-1.279, P = 0.088).

Conclusions: Using a two-sample MR analysis, we investigated the relationship between AILDs and RA and revealed first that PBC increases the risk of RA. Large-scale cross-disease GWAS are required to further illuminate the genomic landscape of AILDs and RA.

Keywords: Autoimmune liver diseases; Causal relationship; Genome-wide association study; Mendelian randomization; Rheumatoid arthritis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Rheumatoid* / genetics
Autoimmune Diseases* / genetics
Genome-Wide Association Study
Humans
Liver Diseases* / genetics
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide