Correlations between genetically predicted lipid-lowering drug targets and inflammatory bowel disease

Abstract

Background: Millions of individuals globally suffer from Inflammatory bowel diseases (IBDs). There is a dearth of large population-based investigations on lipid metabolism and IBDs, and it is unclear whether lipid-lowering drugs target IBDs causally. Consequently, the aim of this study was to investigate the effects of lipid-lowering medication targets on the occurrence and progression of IBDs.

Methods: Among the more than 400,000 participants in the UK Biobank cohort and the more than 170,000 participants in the Global Lipids Genetics Consortium, a total of nine genes linked to lipid-lowering drug targets were obtained (ABCG5/ABCG8, APOB, APOC3, LDLR, LPL, HMGCR, NPC1L1, PCSK9, and PPARA). IBD data were acquired from de Lange et al. (patients/sample size of IBDs: 25042/59957; ulcerative colitis (UC): 12366/45,975; Crohn's disease (CD): 12194/40,266) and the FinnGen cohort (patients/total sample size of IBDs: 4420/176,899; CD: 1520/171,906; UC: 3325/173,711). All four datasets were cross-combined for validation via Mendelian randomization analysis, and potential mediating factors were explored via mediation analysis.

Results: Genetically proxied APOC3 inhibition was related to increased IBD risk (odds ratio (95% confidence interval): 0.87 (0.80-0.95); P < 0.01) and UC risk (0.83 (0.73-0.94); P < 0.01). IBD and CD risk were reduced by genetic mimicry of LDLR and LPL enhancements, respectively (odds ratioLDLR: 1.18 (1.03-1.36); P = 0.018; odds ratioCD: 1.26 (1.11-1.43); P = 2.60E-04). Genetically proxied HMGCR inhibition was associated with increased CD risk (0.68 (0.50-0.94); P = 0.018). These findings were confirmed through Mendelian analysis of the cross-combination of four separate datasets. APOC3-mediated triglyceride levels may contribute to IBDs partly through mediated triglycerides, Clostridium sensu stricto 1, Clostridiaceae 1, or the Lachnospiraceae FCS020 group. LDLR enhancement may contribute to IBDs partly through increasing Lactobacillaceae.

Conclusion: Vigilance is required to prevent adverse effects on IBDs (UC) for patients receiving volanesorsen (an antisense oligonucleotide targeting ApoC3 mRNA) and adverse effects on CD for statin users. LPL and LDLR show promise as candidate drug targets for CD and IBD, respectively, with mechanisms that are potentially independent of their lipid-lowering effects.

Keywords: Inflammatory bowel disease; Lipids; Mendelian randomization.