Low-density lipoprotein cholesterol and risk of gallstone disease: A Mendelian randomization study and meta-analyses

Abstract

Drugs which reduce plasma low-density lipoprotein cholesterol (LDL-C) may protect against gallstone disease. Whether plasma levels of LDL-C per se predict risk of gallstone disease remains unclear. We tested the hypothesis that elevated LDL-C is a causal risk factor for symptomatic gallstone disease. We used a Mendelian randomization approach and genotyped 63,051 individuals from a prospective cohort study of the general Danish population, including 3323 subjects with symptomatic gallstones. We selected eight genetic variants in APOE, APOB, LDLR, and PCSK9 affecting LDL-C. Furthermore, studies of APOE rs429358/rs7412 (defining ε2/ε3/ε4 alleles; 12 studies) and APOB rs693 (eight studies) were included in meta-analyses. The observational hazard ratio (HR) for symptomatic gallstone disease for the fifth versus first quintile of LDL-C was 0.94 (95% confidence interval: 0.76-1.17), despite a corresponding 134% increase in LDL-C. Furthermore, although individual genetic variants in APOE, APOB, LDLR, and PCSK9 associated with stepwise increases/decreases in LDL-C of up to +59% compared with non-carriers (p <0.001), none predicted the risk of symptomatic gallstone disease. Combining all variants into 10 genotypes, carriers of 9 versus ⩽3 LDL-C increasing alleles associated with 41% increased LDL-C (p <0.001), but predicted a HR for symptomatic gallstone disease of 1.09 (0.70-1.69). Finally, in meta-analyses, random effects odds ratios for gallstone disease were 0.91 (0.78-1.06) for carriers of APOE ε4 versus non-carriers, and 1.25 (0.95-1.63) for APOB rs693 CT+TT versus CC. Results from the observational study, genetic studies, and meta-analyses suggest that elevated plasma levels of LDL-C are not causally associated with increased risk of symptomatic gallstone disease.