Association between the use of lipid‐lowering drugs and the risk of inflammatory bowel disease

Abstract Background Observational studies have suggested an association between lipid‐lowering drugs and inflammatory bowel disease (IBD) risk. This study aimed to assess the causal influence of lipid‐lowering agents on IBD risk using Mendelian randomization analysis. Method In a population of 173,082 individuals of European ancestry, 55 single‐nucleotide polymorphisms were identified as instrumental variables for 6 lipid‐lowering drug targets (HMGCR, NPC1LC, PCSK9, LDLR, CETP and APOB). Summary statistics for the genome‐wide association study of IBD, ulcerative colitis (UC) and Crohn's disease (CD) were obtained from the FinnGen consortium, Program in Complex Trait Genomics and UK Biobank. Inverse‐variance weighted was employed as the primary MR method, and odds ratios (ORs) with 95% confidence intervals were reported as the results. Sensitivity analyses using conventional MR methods were conducted to assess result robustness. Results Gene‐proxied inhibition of Niemann‐Pick C1‐like 1 (NPC1L1) was associated with an increased IBD risk (OR [95% CI]: 2.31 [1.38, 3.85]; p = .001), particularly in UC (OR [95% CI]: 2.40 [1.21, 4.74], p = .012), but not in CD. This finding was replicated in the validation cohort. Additionally, gene‐proxied inhibition of low‐density lipoprotein receptor was associated with reduced IBD (OR [95% CI]: .72 [.60, .87], p < .001) and UC risk (OR [95% CI]: .74 [.59, .92], p = .006), although this result was not replicated in the validation cohort. Other drug targets did not show significant associations with IBD, UC or CD risk. Conclusion Inhibition of the lipid‐lowering drug‐target NPC1L1 leads to an increased IBD risk, mainly in the UC population.