Causal associations between changes in lipid profiles and risk of gallstone disease: a two-sample Mendelian randomization study

Abstract

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has been linked to gallstone disease (GSD) in observational studies; however, the relationships between certain lipid profiles and GSD remain unclear. METHODS We adopted a two-sample Mendelian randomization (MR) framework by applying different statistical methods to assess causalities between lipid profiles and GSD. We identified single-nucleotide polymorphisms (SNPs) for blood lipids and NAFLD from separate previous genome-wide association studies (GWASs). RESULTS We retrieved GSD SNPs attributed to 10,520 cases and 361,194 controls and validated our estimates using GWAS summary data from UK Biobank. We also performed sex-stratified analyses. Based on the summary estimates of 41, 59, 35, and 2 SNPs for low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), triglycerides (TGs), and NAFLD, respectively, we found no evidence of a causal relationship between genetically-predicted lipid profiles and GSD. The odds ratios were 0.995 for LDLC [95% confidence interval (CI): 0.994-0.998] per 0.98 mmol/L, 0.999 for HDLC (95% CI: 0.996-1.003) per 0.41 mmol/L, 0.997 for TGs (95% CI: 0.994-1.001) per 1 mmol/L, and 0.993 for NAFLD (95% CI: 0.984-1.003). No evidence of associations between lipid profile s and GSD in validation MR analyses or the sex-stratification analyses was noted. CONCLUSIONS Genetically predicted hyperlipidemia or NAFLD is not causally associated with GSD.