Genetic association of lipid-lowering drug target genes with cholecystitis: A summary-data-based Mendelian randomization analysis

There were some evidences to suggest the correlation between circulating lipid levels and cholecystitis, but no evidence had been indicated the causal relationship between lipid-lowering drugs and cholecystitis. To investigate this, we employed drug target Mendelian randomization (MR), summary-data-based MR (SMR), and genetic colocalization analyses to assess the association between lipid-lowering drugs and cholecystitis. In this study, we used 2 sets of genetic tools to proxy lipid-lowering drugs: elevated high-density lipoprotein cholesterol (CETP), decreased low-density lipoprotein cholesterol (LDLR, HMGCR, NPC1L1, PCSK9, APOB, and ABCG5/ABCG8), and decreased triglycerides (LPL, PPARA, ANGPTL3, and APOC3); the expression quantitative trait locus of target genes from the eQTLGen consortium and Genotype-Tissue Expression project V8. Then, the causal effects of these lipid-lowering drugs genetic proxies on cholecystitis were estimated using a variety of MR, SMR, and colocalization as sensitivity analyses. Collectively, in the MR results, we found that the significant causal effects between genetically proxied ABCG5/ABCG8 enhancement and HMGCR inhibitors were associated with a reduced risk of cholecystitis. The results of SMR and heterogeneity in dependent instruments tests indicated that the expression of ABCG5/ABCG8 and HMGCR in multiple tissues were associated with cholecystitis. In conclusion, our study provides genetic evidence demonstrating a causal relationship between the enhancement of ABCG5/ABCG8 gene proxies and the use of HMGCR inhibitors with a reduced risk of cholecystitis. These findings support the potential reuse of lipid-lowering drugs in patients with cholecystitis and could inform the development of effective treatment strategies for this population in clinical practice.