Introduction: In observational studies, statin treatment is associated with low risk of gallstone disease(GSD).
Hypothesis: We tested the hypothesis that genetic variants in HMGCR, mimicking treatment with statins, was causally associated with low risk of GSD.
Methods: We included 106,588 individuals from the general population. During a median follow-up of 38 years, 6.231 developed symptomatic GSD. We first tested whether statin treatment was associated observationally with GSD. Subsequently, to mimic the effect of statin treatment, we calculated weighted allele scores based on the LDL cholesterol-lowering(=HMGCR inhibitory) effects of each of two variants tagging the HMGCR gene. Finally, we tested the association of the HMGCR allele score with plasma levels of LDL cholesterol, and with risk of GSD. As a positive control, we used the association between the HMGCR allele score and risk of IVD.
Results: Approximately 11% of individuals were on statin treatment. Observationally, statin treatment was associated with a median 28%(0.93 mmol/L) lower LDL cholesterol in treated versus untreated individuals (P<10-300). The corresponding reduction in risk of symptomatic GSD was 24%[hazard ratio(HR): 0.76; 95% confidence interval(CI): 0.64-0.89; P=9x10-4). HMGCR weighted allele scores(beta-coefficients) were associated with stepwise lower LDL cholesterol of up to 4.0%(0.14 mmol/L) in individuals with the lowest versus the highest score(P for trend=2x10-61), and with a corresponding 14%[HR 0.86(95% CI: 0.80-0.93) lower risk of GSD(P for trend=1x10-4). The odds ratio for IVD for the same allele score was 6% lower in individuals with the highest versus the lowest score [HR 0.94(95% CI: 0.89-0.99)] (P for trend 0.02).
Conclusion: Lifelong, genetic inhibiton of HMGCR, mimicking treatment with statins, is associated with low risk of symptomatic GSD. These results suggest that treatment with statins causally lowers risk of GSD in addition to cardiovascular risk.