Rheumatology · Medical Literature
Association between inflammatory bowel disease and ankylosing spondylitis: Mendelian randomization of a different database and meta-analysis.
Abstract
Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) are common autoimmune disorders that have a serious impact on the physical and mental health of patients. Some patients with AS also suffer from IBD, and some studies have shown that there is a link between the 2. However, the causal relationship between the 2 is not clear. This study aimed to infer a causal relationship between IBD and AS using Mendelian randomization (MR) analysis. We obtained genome-wide association study data related to IBD and AS from the Integrative Epidemiology Unit database and the Finnish database to infer the causal relationship between IBD and AS. MR analyses were performed using 3 methods, mainly inverse-variance weighting (IVW). The robustness of causal effects was ensured by multiple methods (instrumental variables were assessed using F-values, heterogeneity was detected by Cochran's Q, horizontal pleiotropy was assessed by MR-Egger regression, and outliers were detected by Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out methods). Subsequently, we selected genome-wide association studies data from 3 different databases for an independent two-sample MR analysis and a meta-analysis based on 3 independent MR estimates to assess the causal relationship between IBD and AS. There was a positive causal relationship between Crohn disease (CD) and AS with IVW results (odds ratio = 1.19, 95% confidence interval = 1.12-1.27; P <.01). There was a positive causal relationship between ulcerative colitis (UC) and AS with IVW results (odds ratio = 1.60, 95% confidence interval = 1.28-2.00; P <.01). Neither CD nor UC had an inverse causal relationship with AS. In order to verify the accuracy of the results, we performed a meta-analysis of the results obtained from the 3 MR analyses, and the results were consistent with the results we had previously obtained. CD and UC may increase the risk of AS.
Clinical relevance
This study addresses the long-observed but causally unconfirmed co-occurrence of inflammatory bowel disease (IBD) and ankylosing spondylitis (AS), two prevalent autoimmune conditions with significant morbidity. Using Mendelian randomization (MR)—a method that leverages genetic variants as instrumental variables to minimize confounding—the authors provide evidence for a directional causal relationship from IBD to AS, not the reverse. Rheumatologists and gastroenterologists should be aware of this finding as it has direct implications for screening, interdisciplinary monitoring, and potentially earlier immunomodulatory intervention in at-risk patients.
Key findings
1. Crohn's disease (CD) demonstrated a statistically significant positive causal effect on AS risk by inverse-variance weighting (IVW): OR = 1.19 (95% CI: 1.12–1.27; P < .01), indicating an approximately 19% increased odds of AS per unit increase in genetically instrumented CD liability. 2. Ulcerative colitis (UC) demonstrated a stronger positive causal effect on AS risk by IVW: OR = 1.60 (95% CI: 1.28–2.00; P < .01), indicating an approximately 60% increased odds of AS per unit increase in genetically instrumented UC liability. 3. Instrument validity was assessed using F-statistics, with Cochran's Q test employed to detect heterogeneity among instrumental variables across all MR analyses. 4. Horizontal pleiotropy—a key potential confound in MR studies—was evaluated using MR-Egger regression intercept, and outliers were identified via the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) method and leave-one-out sensitivity analyses, supporting the robustness of the causal estimates. 5. Neither CD nor UC demonstrated an inverse (reverse) causal relationship with AS, suggesting the directionality of causation runs from IBD to AS and not from AS to IBD. 6. An independent two-sample MR analysis drawing on three distinct GWAS databases (IEU, Finnish, and a third independent database), followed by meta-analysis of all three MR estimates, yielded results consistent with the primary analysis, reinforcing that both CD and UC may causally increase AS risk.
Practice implications
Gastroenterologists managing patients with established CD or UC—particularly UC, given the higher estimated OR of 1.60—should implement routine, structured screening for axial spondyloarthropathy symptoms (inflammatory back pain, morning stiffness, limited spinal mobility) and consider early referral to rheumatology, as a significant proportion may be at genetically mediated elevated risk for AS. Rheumatologists evaluating new AS diagnoses should prospectively inquire about bowel symptoms and coordinate with gastroenterology, as the causal directionality identified here suggests IBD may precede or drive AS onset rather than simply co-occur. These findings also support the prioritization of biologic therapies with dual efficacy in both IBD and AS (e.g., TNF-α inhibitors, IL-12/23 or IL-17 inhibitors with appropriate IBD-specific evidence) in patients presenting with overlapping disease, though prospective clinical trials are needed to validate treatment-selection strategies based on this causal model.