Causal Link between Inflammatory Bowel Disease and Fistula: Evidence from Mendelian Randomization Study

Background: Previous observational studies have found that fistulas are common in Crohn’s disease (CD) and less common in ulcerative colitis (UC). However, some patients have a fistula before diagnosis. Based on retrospective analysis, it was not possible to determine whether there was a bi-directional causal relationship between inflammatory bowel disease (IBD) and fistulas. Methods: Data were extracted from the open GWAS database; 25,042 cases and 34,915 controls were included for IBD, and 6926 cases and 30,228 controls were included for fistula. Two-sample Mendelian randomization and multivariable Mendelian randomization were used in combination to determine the causal relationship between IBD and fistula. Results: Forward MR showed that IBD increased the risk of colonic or urogenital fistula (FISTULA) (OR: 1.09, 95% CI: 1.05 to 1.13, p = 1.22 × 10(−6)), mainly associated with fissure and fistula of the anal and rectal regions (FISSANAL) (OR:1.10, 95% CI:1.06 to 1.14, p = 6.12 × 10(−8)), but not with fistulas involving the female genital tract (FEMGENFISTUL) (OR:0.97, 95% CI: 0.85 to 1.11, p = 0.669). Furthermore, both UC and CD increased the risk of FISTULA. However, after adjusting by MVMR, only CD increased the risk of FISTULA (OR: 1.06, 95% CI: 1.02 to 1.11, p = 0.004), and UC did not increase the risk of FISTULA (OR: 1.01, 95% CI: 0.95 to 1.06, p = 0.838). Reverse MR showed that fistulas did not increase the risk of IBD. Conclusion: Our study confirms it is CD, rather than UC, that casually leads to an increased risk of fistula, but fistulas do not increase the risk of IBD.