Evaluating the Causal Association between Inflammatory Bowel Disease and Risk of Atherosclerotic Cardiovascular Disease: Univariable and Multivariable Mendelian Randomization Study

Baike Liu; Zijian Qin; Zhaolun Cai; Zheran Liu; Yun-Lin Chen; Xiaonan Yin; Yuan Yin; Xingchen Peng; Bo Zhang

doi:10.3390/biomedicines11092543

Evaluating the Causal Association between Inflammatory Bowel Disease and Risk of Atherosclerotic Cardiovascular Disease: Univariable and Multivariable Mendelian Randomization Study

Biomedicines. 2023 Sep 15;11(9):2543. doi: 10.3390/biomedicines11092543.

Authors

Baike Liu^{1

2}, Zijian Qin³, Zhaolun Cai^{1

2}, Zheran Liu³, Yun-Lin Chen⁴, Xiaonan Yin^{1

2}, Yuan Yin^{1

2}, Xingchen Peng³, Bo Zhang^{1

2}

Affiliations

¹ Gastric Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
² State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
³ Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
⁴ Department of Cardiology, The 2nd Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.

Abstract

Background: Observational studies suggested that inflammatory bowel disease (IBD) (i.e., Crohn's disease [CD] and ulcerative colitis [UC]) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease (CAD) and ischemic stroke. However, it is still unclear whether the observed associations causally exist. Thus, we aim to examine the potential effect of IBD, CD, and UC on the risk of CAD and ischemic stroke, using a two-sample Mendelian randomization (MR) study.

Methods: Genetic instruments for IBD, CD, and UC were retrieved from the latest published genome-wide association studies (GWASs) of European ancestry. GWAS summary data for instrument-outcome associations were gathered from four independent resources: CARDIoGRAMplusC4D Consortium, MEGASTROKE consortium, FinnGen, and UK Biobank. The inverse variance weighted (IVW) method and multiple pleiotropy-robust approaches were conducted and, subsequently, combined in a fixed-effect meta-analysis. Moreover, multivariable MR (MVMR) analysis was conducted to adjust for potential influencing instrumental variables.

Results: The IVW method revealed no causal effect of IBD on the risk of CAD (overall IBD on CAD: OR 1.003, 95%CI 0.982 to 1.025; CD on CAD: OR 0.997, 95%CI 0.978 to 1.016; UC on CAD: OR 0.986, 95%CI 0.963 to 1.010) or the risk of ischemic stroke (overall IBD on ischemic stroke: OR 0.994, 95%CI 0.970 to 1.018; CD on ischemic stroke: OR 0.996, 95%CI 0.979 to 1.014; UC on ischemic stroke: OR 0.999, 95%CI 0.978 to 1.020). The results of the meta-analysis and MVMR remained consistent.

Conclusion: Our MR analysis does not support a causal effect of IBD on CAD and ischemic stroke, and previous results from observational studies might be biased through uncontrolled confoundings (such as IBD-specific medications and detection bias, etc.) that warrant further research.

Keywords: Crohn’s disease; Mendelian randomization study; atherosclerotic cardiovascular disease; coronary artery disease; inflammatory bowel disease; ischemic stroke; ulcerative colitis.

Grants and funding

No. 2022YFS2010, No. 2021YFS0224/Sichuan University