Repurposing statin treatment for the prevention of gallstone disease

BACKGROUND AND AIMS: In observational studies, statin treatment has been associated with low risk of gallstone disease (GSD) or cholecystectomy. We tested the hypothesis that genetic variation in HMGCR, mimicking statin treatment, causally lowers risk of GSD and cholecystectomy in the general population.

METHODS: A drug-target Mendelian randomization analysis was conducted using individual participant data on 101,809 and 375,094 individuals from the Copenhagen General Population Study (CGPS) and the UK Biobank (UKBB), followed for a median 44 and 26 years, respectively, with external validation using summary level data from up to 1,319,534 individuals. The exposure was HMGCR rs12654264A>T, a GWAS variant strongly associated with LDL cholesterol (LDL-C) in the Global Lipids Genetics Consortium. Endpoints were incident GSD and cholecystectomy, with myocardial infarction (MI) as a positive control.

RESULTS: Using instrumental variable analysis, a 1 standard deviation (SD) lower LDL-C due to statin treatment was observationally associated with a 21 % and 16 % lower risk of GSD [Odds Ratio (OR) = 0.79(95 % CI:0.66-0.95)]; 0.84(0.78-0.91)] in the CGPS and UKBB, respectively. The corresponding risk of cholecystectomy was lower by 12 % [0.88(0.69-1.11)] and 23 % [0.77(0.71-0.84)] in the CGPS and UKBB, respectively. In meta-analyses, the ORs per 1 SD lower LDL-C via HMGCR were 0.63(0.46-0.86) for GSD and 0.68(0.52-0.88) for cholecystectomy, similar to the OR for MI of 0.75(0.63-0.88).

CONCLUSIONS: Statin treatment likely causally reduces risk of GSD and cholecystectomy in the general population. Furthermore, lowering LDL-C by statin treatment may be as effective in the prevention of GSD and cholecystectomy as in the prevention of MI.