Genetic RA Associated With Inflammatory Bowel Disease, but Not Other Way Around

The genetically-predicted risk of rheumatoid arthritis (RA) was positively associated with an increased risk of inflammatory bowel disease (IBD), a study published in Seminars in Arthritis & Rheumatism found.

The association was seen with IBD as a whole and potentially with its main subtypes, ulcerative colitis (UC) and Crohn disease (CD). While this suggests RA has a causal role in the pathogenesis of IBD, the authors noted that IBD was not found to have a causal role in the development of RA.

This finding contradicts that of a previous meta-analysis that claimed individuals with IBD had an increased risk of developing RA compared with individuals without IBD. However, it was noted there was “substantial” heterogeneity across the studies included in that review.

“So far, no systematic evaluation and meta-analysis of studies was conducted to determine the risk of IBD in patients suffering from RA,” the authors of the newer review said. “The present study extends prior research by showing a causal relationship between RA and IBD, although the pathophysiological mechanisms underlying this relationship are not entirely clear.”

These authors conducted a Mendelian randomization (MR) analysis, which uses genetic variants to strengthen causal inference. This method also ensures that the genetic variant is strongly associated with the exposure, influences the outcome only through exposure, and is not associated with a confounder of the risk factor-outcome association.

A genome-wide association study (GWAS) included 29,880 individuals with RA and 73,758 control patients without RA. For IBD, another GWAS included data on 12,882 individuals with general IBD and 21,770 control patients without IBD, as well as 5956 patients with CD and 14,927 without, and 6968 with UC and 20,464 without. Both studies only included individuals of European descent.

The authors found a 19.5% genetic correlation between CD and UC, which they deemed weak and led them to believe that the 2 IBD subtypes are not expected to co-occur systematically.

Pleiotropy, or when 1 gene produces multiple, seemingly unrelated phenotype traits, was also considered in this analysis. Genetic instruments in the bidirectional analyses single nucleotide polymorphism (SNPs) were selected at the genome-wide significance threshold of P < 5x10^-8.

After removing pleiotropic SNPs, genetically-predicted RA was positively associated with IBD as a whole (OR, 1.214; 95% CI, 1.134-1.299; P = 3x10^-8).

In terms of the 2 IBD subtypes, RA was suggestively positively associated with CD (OR, 1.108; 95% CI, 1.024-1.199; P = .011) and UC (OR, 1.082; 95% CI, 1.002-1.168; P = .044). However, no associations were made in the other direction between IBD as a whole or both subtypes and RA.

The authors said a major strength of their study was using a bidirectional 2-sample MR approach, as opposed to observational research.

“We applied an iterative approach, which was conservative, minimized the heterogeneity, confirmed the consistency of point estimates before and after outlier removal and thus strengthened the evidence,” they said. “Furthermore, we conducted a number of sensitivity analyses to ensure the consistency of causal estimates and confirm robustness of the present findings.”

However a major limitation is the role of pleiotropy. While it appeared to not play a role in the current findings as sensitivity analyses were consistent, a notable amount of SNPs that were considered pleiotropic were excluded, potentially resulting in an over-precision of causal estimates. An independent MR analysis identifying pleiotropic SNPs was conducted and confirmed the review’s significant findings.

Overall, these findings are a next step encouraging further research in genetically-predicted RA and have clinical implications.

“In patients with RA it is important that physicians and practitioners pay attention to the development of IBD in patients with this disease,” the authors concluded. “The results of the present study thus may contribute to more timely preventive care and better interdisciplinary, holistic patient management.”

Reference

Meisinger C, Freuer D. Rheumatoid arthritis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study. Semin Arthritis Rheum. Published online March 9, 2022. doi:10.1016/j.semarthrit.2022.151992