Causal Linkage Between Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Two-Sample Mendelian Randomization Analysis

Ying Xie; Xuejie Chen; Minzi Deng; Yuhao Sun; Xiaoyan Wang; Jie Chen; Changzheng Yuan; Therese Hesketh

doi:10.3389/fgene.2021.649376

Causal Linkage Between Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Two-Sample Mendelian Randomization Analysis

Front Genet. 2021 Mar 18:12:649376. doi: 10.3389/fgene.2021.649376. eCollection 2021.

Authors

Ying Xie¹, Xuejie Chen², Minzi Deng², Yuhao Sun¹, Xiaoyan Wang², Jie Chen¹, Changzheng Yuan³, Therese Hesketh^{1

4}

Affiliations

¹ Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China.
² Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Department of Big Data and Health Science, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Institute for Global Health, University College London, London, United Kingdom.

Abstract

Background: Observational studies suggest an association between inflammatory bowel disease (IBD) [including ulcerative colitis (UC) and Crohn's disease (CD)] and Primary sclerosing cholangitis (PSC), but the causal association between the two diseases remains unclear.

Methods: We used two-sample Mendelian randomization (MR) to estimate the causal association between IBD and PSC. We chose single nucleotide polymorphisms (SNPs) data for analysis, obtained from previous genome-wide association studies (GWASs). Pleiotropy, heterogeneity, and sensitivity analyses were performed for quality control.

Results: We found that the causal associations between IBD (both UC and CD) and PSC were significant (e.g., IBD and PSC, Robust adjusted profile score (RAPS) OR = 1.29, 95% CI 1.16∼1.44, p< 0.01; UC and PSC, RAPS OR = 1.40, 95% CI 1.23∼1.58, p< 0.01; CD and PSC, RAPS OR = 1.13, 95% CI 1.02∼1.26, p = 0.02). MR Egger, IVW, and ML tests found statistical heterogeneity between determined IV estimates. The leave-one-out analysis also indicated the sensitivity of the SNPs (e.g., IBD and PSC, MR-Egger Q = 644.30, p< 0.01; UC and PSC, MR-Egger Q = 378.30, p< 0.01; UC and PSC, MR-Egger Q = 538.50, p < 0.01).

Conclusion: MR analyses support the positive causal effect of IBD (including UC and CD) on PSC in a European population. We provide suggestions for preventing and treating the two diseases.

Keywords: Crohn’s disease; inflammatory bowel disease; mendelian randomization; primary sclerosing cholangitis; ulcerative colitis.