title: Elevated body mass index as a causal risk factor for symptomatic gallstone disease: a Mendelian randomization study.
abstract: Elevated body mass index (BMI) is associated with an increased risk of gallstone disease. 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 for each participant. In observational analyses, mean baseline BMI was 55% (11.6 kg/m(2) ) 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 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/m(2) ) 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/m(2) increase in genetically determined BMI, 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.
  
  
  CONCLUSIONS
  These results are compatible with a causal association between elevated BMI and increased risk of symptomatic gallstone disease, which is most pronounced in women.
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stender
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjaerg-Hansen
mesh_terms: D000368:Aged; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D015986:Confounding Factors, Epidemiologic; D003718:Denmark; D005260:Female; D042882:Gallstones / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009765:Obesity / Q000150:complications* / Q000235:genetics; D016017:Odds Ratio; D011506:Proteins / Q000235:genetics; D011897:Random Allocation; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D012307:Risk Factors
chemical_list: C470072:MC4R protein, human; D008565:Membrane Proteins; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; C530715:TMEM18 protein, human; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human