3). There was no statistically significant interaction between allele score and sex on risk of symptomatic gallstone disease (P = 0.49). Associations of the individual genotypes are shown in the Supporting Figure. We examined the potential causal effect of increased BMI on risk of symptomatic gallstone disease in instrumental variable analyses (Fig. 5). Causal ORs

for a 1-kg/m2 increase in genetically determined BMI were 1.17 (95% CI: 0.99-1.37) overall and 1.20 (95% CI: 1.00-1.44) and 1.02 (95% CI: 0.90-1.16) in women and men, respectively (Fig. 5). The corresponding observed multifactorially adjusted HRs for symptomatic gallstone disease for a 1-kg/m2 increase in BMI were 1.07 (95% CI: 1.06-1.08) overall and 1.08 (95% CI: 1.07-1.10) and 1.04 (95% CI: 1.02-1.07) 3-Methyladenine cost in women and men, respectively. The novel finding of this study of 77,679 individuals from the general population, including 4,106 learn more with symptomatic gallstone disease, is that genetically elevated BMI is associated with increased risk of symptomatic gallstone disease, compatible with a causal association between elevated BMI and increased risk of symptomatic gallstones. Obesity is known to be associated with gallstone disease

in observational epidemiology.[1-5] However, a range of environmental, socioeconomic, and/or behavioural factors that are associated with obesity may also influence risk of gallstone disease. This makes it difficult to determine whether obesity per se is causally involved in gallstone disease. To overcome this inherent limitation of observational epidemiology, we used the Mendelian randomization approach,[8] a design that uses genetic variants that are associated with BMI, but not with potential confounding factors, as instruments to examine the effect of lifelong elevated BMI on risk of symptomatic gallstone disease. Lonafarnib in vivo In our Mendelian randomization study, the risk of symptomatic gallstone disease was increased 7% for every 1-kg/m2 increase in measured BMI (the observational estimate). The corresponding risk increase for every 1 kg/m2 in genetically determined BMI was 17% (the causal, genetic estimate). The concordance

between the observational and genetic estimates supports that increased BMI per se is a causal risk factor for symptomatic gallstone disease, particularly because genetically elevated BMI even seemed to have a larger effect size on symptomatic gallstone disease than the effect size from observational analyses. Numerous explanations for how obesity may influence gallstone formation have been proposed. Obesity may increase hepatic de novo cholesterol synthesis and hepatobiliary cholesterol efflux, a key event in the development of cholesterol gallstones.[15] Increased abdominal fat mass may cause gallbladder hypomotility and bile stasis, another risk factor for gallstone formation, a hypothesis that is supported by some,[16] but not all,[17] previous studies. Weight cycling (i.e.