Assessment of Causal Relationship Between Rheumatoid Arthritis and Inflammatory Bowel Disease: A Bi-Directional Mendelian Randomization Study

Abstract

Objective: Observational studies have shown that rheumatoid arthritis (RA) was associated with a higher risk of inflammatory bowel disease (IBD), and vice versa. However, if such associations reflect causality remains unclear. We aimed to examine the bidirectional causal associations of RA with IBD, ulcerative colitis (UC), and Crohn’s disease (CD).Method: A Bi-directional Mendelian randomization (MR) analysis and Linkage Disequilibrium Score regression (LDSC) were used to investigate the causality between RA and IBD subtypes. Summary data was extracted from the Rheumatoid Arthritis Consortium International for Immunochip (RACI) consortium and the Genetics and Allied research in Rheumatic diseases Networking (GARNET) consortium (29,880 cases of RA and 73,758 controls); and the International IBD Genetics Consortium (38,155 cases of IBD and 48,485 controls; 17,647 cases of UC and 47,179 controls; 20,550 cases of CD and 41,642 controls). Results: Genetically predicted RA was associated with higher risks of IBD (per 1-unit higher log odds: odds ratio: 1.13; 95% confidence interval: 1.04-1.21; P=0.002) and UC (1.16; 1.07-1.25; P=1.5 × 10−4) after a Bonferroni correction (P<0.05/3). In addition, the weighted median method showed a suggestive association of RA with a higher risk of CD (1.16; 1.05-1.28; P=0.003). However, there was no evidence showing a causal relation of IBD, UC or CD with RA risk. Conclusion: Our findings provide novel evidence supporting a significant causality of RA with IBD or UC, whereas IBD is unlikely to increase the risk of RA, indicating the importance of keeping gut microbiota composition healthy for RA patients to prevent IBD.