Lipids, lipid-lowering agents, and inflammatory bowel disease: a Mendelian randomization study

Heqing Tao; Zhou Yu; Yongqiang Dong; Ligang Liu; Liang Peng; Xueqing Chen

doi:10.3389/fimmu.2023.1160312

Lipids, lipid-lowering agents, and inflammatory bowel disease: a Mendelian randomization study

Front Immunol. 2023 Jun 7:14:1160312. doi: 10.3389/fimmu.2023.1160312. eCollection 2023.

Authors

Heqing Tao¹, Zhou Yu², Yongqiang Dong³, Ligang Liu⁴, Liang Peng¹, Xueqing Chen¹

Affiliations

¹ Department of Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
² Department of Neurology, Peking University Third Hospital, Beijing, China.
³ Deartment of Thyroid Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Institute of Therapeutic Innovations and Outcomes, College of Pharmacy, The Ohio State University, Columbus, OH, United States.

Abstract

Background: To assess the causal role of lipid traits and lipid-lowering agents in inflammatory bowel disease (IBD).

Methods: Univariable mendelian randomization (MR) and multivariable MR (MVMR) analyses were conducted to evaluate the causal association between low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and IBD. Drug-targeted MR analyzed the effects of lipid-lowering drugs on IBD, and network MR was used to analyze potential mediation effects.

Results: The levels of HDL-C had an inverse relationship with the risk of Crohn's disease (CD, OR: 0.85, 95% CI: 0.73-0.98, P = 0.024). In MVMR, the inverse relationships were found in all three outcomes. Drug-targeted MR analyses showed that with one-SD LDL-C decrease predicted by variants at or near proprotein convertase subtilisin/kexin type 9 (PCSK9), the OR values of people diagnosed with IBD, ulcerative colitis (UC) and CD were 1.75 (95%CI: 1.13-2.69, P = 0.011), 2.1 (95%CI: 1.28-3.42, P = 0.003) and 2.24 (95%CI: 1.11-4.5, P = 0.024), respectively. With one-SD LDL-C decrease predicted by variants at or near cholesteryl ester transfer protein (CETP), the OR value of people diagnosed with CD was 0.12 (95%CI: 0.03-0.51, P = 0.004). Network-MR showed that HDL-C mediated the causal pathway from variants at or near CETP to CD.

Conclusion: Our study suggested a causal association between HDL-C and IBD, UC and CD. Genetically proxied inhibition of PCSK9 increased the risk of IBD, UC and CD, while inhibition of CETP decreased the risk of CD. Further studies are needed to clarify the long-term effect of lipid-lowering drugs on the gastrointestinal disorders.

Keywords: CTEP 2; Mendelian randomization; PCSK9; inflammatory bowel disease; lipid-lowering; lipids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cholesterol, HDL
Cholesterol, LDL
Humans
Hypolipidemic Agents / therapeutic use
Inflammatory Bowel Diseases* / drug therapy
Inflammatory Bowel Diseases* / genetics
Mendelian Randomization Analysis
Proprotein Convertase 9* / genetics
Risk Factors

Substances

PCSK9 protein, human
Proprotein Convertase 9
Cholesterol, LDL
Hypolipidemic Agents
Cholesterol, HDL

Grants and funding

This study was supported in part by a grant from the Guangdong Natural Science Foundation(2018A030313970) and (2021A1515110491) managed by LP and HT, National Natural Science Foundation of the P.R. China (81900521) and Programs for Science and Technology Development of Henan province (SBJ202003033) managed by YD. The funders of the study had no role in the study design, data collection, analysis, interpretation, writing of the report, or decision to submit for publication.