Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Hepatology. 2013 Dec;58(6):2133-41. doi: 10.1002/hep.26563. Epub 2013 Oct 11.
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: BMIsex 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 scoresex 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.
These results are compatible with a causal association between elevated BMI and increased risk of symptomatic gallstone disease, which is most pronounced in women.
探讨体质量指数（BMI）与胆囊疾病风险增加之间的关系。
采用孟德尔随机化方法，对来自普通人群的 77679 名个体进行研究。在长达 34 年的随访期间，4106 人发生了有症状的胆囊疾病。对三个与 BMI 相关的常见变异体（FTO(rs9939609)；MC4R(rs17782313)；和 TMEM18(rs6548238)）进行了基因分型。为每个参与者计算 BMI 增加等位基因的数量。在观察性分析中，第五个五分位组与第一个五分位组相比，基线 BMI 平均增加了 55%（11.6kg/m2），在男性和女性中相似。总体而言，有症状胆囊疾病的多因素调整后的风险比（HR）为 2.84（95%置信区间[CI]：2.32-3.46），女性为 3.36（95%CI：2.62-4.31），男性为 1.51（95%CI：1.09-2.11）（P趋势：0.001至<0.001；P交互作用：BMI性别对风险的影响=0.01）。在遗传分析中，携带 6 个而非 0-1 个 BMI 增加等位基因与 BMI 总体增加 5.2%（1.3kg/m2）有关，在女性中增加 4.3%，在男性中增加 6.1%（均 P趋势：<0.001）。有症状胆囊疾病的相应 HR 为 1.43（95%CI：0.99-2.05），女性为 1.54（95%CI：1.00-2.35），男性为 1.19（95%CI：0.60-2.38）（P趋势=0.007、0.02 和 0.26，P 交互作用等位基因评分性别对风险的影响=0.49）。通过对遗传决定 BMI 每增加 1kg/m2 的工具变量分析，有症状胆囊疾病的因果比值比（OR）估计值为 1.17（95%CI：0.99-1.37），总体为 1.20（95%CI：1.00-1.44），女性和男性分别为 1.02（95%CI：0.90-1.16）。相应的观察性 HR 分别为 1.07（95%CI：1.06-1.08）、1.08（95%CI：1.07-1.10）和 1.04（95%CI：1.02-1.07）。
这些结果与 BMI 升高与胆囊疾病风险增加之间存在因果关系的观点相一致，且在女性中最为明显。
