Whether this reflects a causal association is unknown. Using a Mendelian randomization approach, we studied 77,679 individuals from the general population. Of these, 4,106 developed symptomatic gallstone disease during up to 34 years of follow-up.

Subjects were genotyped for three common variants known to associate with BMI: FTO(rs9939609); MC4R(rs17782313); and TMEM18(rs6548238). The number of BMI-increasing alleles was calculated Bortezomib ic50 for each participant. In observational analyses, mean baseline BMI was 55% (11.6 kg/m2) increased in individuals in the fifth quintile versus the first quintile, similar in women and men. The corresponding multifactorially adjusted hazard ratio (HR) for symptomatic gallstone disease PD0325901 in vitro was 2.84 (95% confidence interval [CI]: 2.32-3.46) overall,

3.36 (95% CI: 2.62-4.31) in women, and 1.51 (95% CI: 1.09-2.11) in men (P trend: 0.001 to <0.001; P interaction: BMI*sex on risk = 0.01). In genetic analyses, carrying 6 versus 0-1 BMI-increasing alleles was associated with a 5.2% (1.3 kg/m2) increase in BMI overall and with increases of 4.3% in women and 6.1% in men (all P trend: <0.001). Corresponding HRs for symptomatic gallstone disease were 1.43 (95% CI: 0.99-2.05) overall, 1.54 (95% CI: 1.00-2.35) in women, and 1.19 (95% CI: 0.60-2.38) in men (P trend = 0.007, 0.02, and 0.26, respectively; P interaction allele score*sex on risk = 0.49). The estimated causal odds ratio (OR) for symptomatic gallstone disease, by instrumental variable analysis for a 1 kg/m2

increase in genetically determined BMI, medchemexpress was 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. Corresponding observational HRs were 1.07 (95% CI: 1.06-1.08), 1.08 (95% CI: 1.07-1.10), and 1.04 (95% CI: 1.02-1.07), respectively. Conclusion: These results are compatible with a causal association between elevated BMI and increased risk of symptomatic gallstone disease, which is most pronounced in women. (Hepatology 2013; 58:2133–2141) Elevated body mass index (BMI) is associated with an increased risk of gallstone disease, one of the most common and costly of gastrointestinal diseases.[1-5] However, whether this association reflects a causal effect of obesity on gallstone disease is unclear. It may be that another factor simultaneously raises BMI and causes gallstone disease, and that elevated BMI is merely a marker of this other causal factor (in epidemiology, this common phenomenon is termed “confounding”). For instance, a high-fat diet might cause obesity as well as changes in the bile composition that promote the formation of cholesterol gallstones.[6] Likewise, physical inactivity is known to be associated with both obesity and gallstone disease and thus constitutes another potential confounder.[7] Apart from confounding, reverse causation could also explain part of the association between BMI and gallstone disease in retrospective or cross-sectional studies (i.e.