AUTHOR=Tao Heqing , Yu Zhou , Dong Yongqiang , Liu Ligang , Peng Liang , Chen Xueqing 

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

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1160312

DOI=10.3389/fimmu.2023.1160312

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>To assess the causal role of lipid traits and lipid-lowering agents in inflammatory bowel disease (IBD).</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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, <italic>P</italic> = 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 (<italic>PCSK9)</italic>, the OR values of people diagnosed with IBD, ulcerative colitis (UC) and CD were 1.75 (95%CI: 1.13-2.69, <italic>P</italic> = 0.011), 2.1 (95%CI: 1.28-3.42, <italic>P</italic> = 0.003) and 2.24 (95%CI: 1.11-4.5, <italic>P</italic> = 0.024), respectively. With one-SD LDL-C decrease predicted by variants at or near cholesteryl ester transfer protein <italic>(CETP)</italic>, the OR value of people diagnosed with CD was 0.12 (95%CI: 0.03-0.51, <italic>P</italic> = 0.004). Network-MR showed that HDL-C mediated the causal pathway from variants at or near <italic>CETP</italic> to CD.</p></sec><sec><title>Conclusion</title><p>Our study suggested a causal association between HDL-C and IBD, UC and CD. Genetically proxied inhibition of <italic>PCSK9</italic> increased the risk of IBD, UC and CD, while inhibition of <italic>CETP</italic> decreased the risk of CD. Further studies are needed to clarify the long-term effect of lipid-lowering drugs on the gastrointestinal disorders.</p></sec>