Obesity, Adiposity, and Risk of Symptomatic Gallstone Disease According to Genetic Susceptibility.

BACKGROUND & AIMS: Adiposity has been consistently associated with gallstone disease risk. We aimed to characterize associations of anthropometric measures (body mass index [BMI], recent weight change, long-term weight change, waist circumference, and waist-to-hip ratio) with symptomatic gallstone disease according to strata of gallstone disease polygenic risk score (PRS). METHODS: We conducted analysis among 34,626 participants with available genome-wide genetic data within 3 large, prospective, U.S. cohorts-the Nurses' Health Study (NHS), Health Professionals Follow-Up Study, and NHS II. We characterized joint associations of PRS and anthropometric measures and tested for interactions on the relative and absolute risk scales. RESULTS: Women in the highest BMI and PRS categories (BMI ≥30 kg/m2 and PRS ≥1 SD above mean) had odds ratio for gallstone disease of 5.55 (95% confidence interval, 5.29 to 5.81) compared with those in the lowest BMI and PRS categories (BMI <25 kg/m2 and PRS <1 SD below the mean). The corresponding odds ratio among men was 1.65 (95% confidence interval, 1.02 to 2.29). Associations for BMI did not vary within strata of PRS on the relative risk scale. On the absolute risk scale, the incidence rate difference between obese and normal-weight individuals was 1086 per 100,000 person-years within the highest PRS category, compared with 666 per 100,000 person-years in the lowest PRS category, with strong evidence for interaction with the ABCG8 locus. CONCLUSIONS: While maintenance of a healthy body weight reduces gallstone disease risk among all individuals, risk reduction is higher among the subset with greater genetic susceptibility to gallstone disease.