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. 2023 Mar 24;12(7):2482.
doi: 10.3390/jcm12072482.

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

Zongbiao Tan  1 , Shijie Zhu  2 , Chuan Liu  1 , Yang Meng  3 , Jiao Li  1 , Jixiang Zhang  1 , Weiguo Dong  1
Affiliations

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

Zongbiao Tan et al. J Clin Med. .

Abstract

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.

Keywords: Mendelian randomization; fistula; genetic epidemiology; inflammatory bowel disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The workflow of this study.
Figure 2
Figure 2
Mendelian randomization (MR) results of IVW. Causal estimation of IBD effects on fistulas (IBD: inflammatory bowel disease; UC: ulcerative colitis; CD: Crohn’s disease; FISTULA: colonic or urogenital fistula; FISSANAL: fissure and fistula of anal and rectal region; FEMGENFISTUL: fistula involving female genital tract; NSNP: the number of single nucleotide polymorphisms used in MR analysis; OR: odds ratio; CI: confidence interval).
Figure 3
Figure 3
Multivariable Mendelian randomization (MVMR) results. Causal estimation of IBD subtype effects on fistulas (IBD: inflammatory bowel disease; UC: ulcerative colitis, CD: Crohn’s disease; FISTULA: colonic or urogenital fistula; FISSANAL: fissure and fistula of anal and rectal regions; FEMGENFISTUL: fistula involving female genital tract; NSNP: the number of single nucleotide polymorphisms used in MR analysis; OR: odds ratio; CI: confidence interval).
Figure 4
Figure 4
Mendelian randomization (MR) results of IVW. Causal estimation of fistula effects on IBD (IBD: inflammatory bowel disease; UC: ulcerative colitis; CD: Crohn’s disease; FISTULA: colonic or urogenital fistula; FISSANAL: fissure and fistula of anal and rectal regions; FEMGENFISTUL: fistula involving female genital tract; NSNP: the number of single nucleotide polymorphisms used in MR analysis; OR: odds ratio; CI: confidence interval).
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