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Causal Link between Inflammatory Bowel Disease and Fistula: Evidence from Mendelian Randomization Study
Zongbiao Tan1, Shijie Zhu2, Chuan Liu1
1Department of Gastroenterology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, China.
Insights
Crohn's disease (CD) causally increases fistula risk, while ulcerative colitis (UC) does not. Fistulas, however, do not appear to increase the risk of developing inflammatory bowel disease (IBD).
Area of Science:
- Gastroenterology
- Genetics
- Epidemiology
Background:
- Fistulas are frequently observed in Crohn's disease (CD) and less so in ulcerative colitis (UC).
- The precise causal relationship between inflammatory bowel disease (IBD) and fistula formation remains unclear.
- Some patients present with fistulas prior to an IBD diagnosis, complicating etiological determination.
Purpose of the Study:
- To investigate the potential causal link between IBD and fistula development.
- To differentiate the specific roles of CD and UC in fistula etiology.
- To assess whether fistulas can causally lead to IBD.
Main Methods:
- Utilized two-sample and multivariable Mendelian randomization (MR) analyses.
- Data were sourced from the open GWAS database, including 25,042 IBD cases and 34,915 controls, and 6926 fistula cases and 30,228 controls.
- MR analyses were performed to infer causal relationships between IBD subtypes and fistula development.
Main Results:
- Inflammatory bowel disease (IBD) was found to increase the risk of colonic or urogenital fistula (FISTULA).
- Crohn's disease (CD) significantly increased fistula risk, particularly anal and rectal fistulas, whereas ulcerative colitis (UC) did not.
- Reverse Mendelian randomization indicated that fistulas do not causally increase the risk of developing IBD.
Conclusions:
- This study establishes a causal link where Crohn's disease (CD) increases the risk of fistula formation.
- Ulcerative colitis (UC) does not demonstrate a causal relationship with increased fistula risk.
- Fistula development does not appear to be a causal factor for inflammatory bowel disease (IBD).
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.
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