The class
Mendelian randomization finds genetically proxied CETP inhibition, mediated through HDL cholesterol, reduces Crohn's disease risk (Front Immunol 2023)
Original title: Lipids, lipid-lowering agents, and inflammatory bowel disease: a Mendelian randomization study
Using univariable and multivariable Mendelian randomization plus drug-target and network Mendelian randomization, researchers assessed causal relationships between lipid traits, lipid-lowering drugs and inflammatory bowel disease (IBD). Higher HDL cholesterol was inversely associated with Crohn's disease risk (odds ratio 0.85, P equals 0.024), an association confirmed in multivariable analysis for all three IBD outcomes. Drug-target analyses found that genetically proxied PCSK9 inhibition, via a one-SD LDL cholesterol decrease, INCREASED risk of IBD, ulcerative colitis and Crohn's disease (odds ratios 1.75 to 2.24), whereas the equivalent LDL-lowering effect of CETP inhibition DECREASED Crohn's disease risk (odds ratio 0.12, P equals 0.004), with network Mendelian randomization showing this CETP-to-Crohn's-disease pathway was mediated by HDL cholesterol, in contrast to PCSK9's harmful association.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.