Independent association of general and central adiposity with risk of gallstone disease: observational and genetic analyses

作者：Min Zhang, Ye Bai, Yutong Wang, Huijie Cui, Wenqiang Zhang, Li Zhang, Peijing Yan, Mingshuang Tang, Yunjie Liu, Xia Jiang, Ben Zhang · 发表于：Frontiers in Endocrinology · 年份：2024 · DOI：10.3389/fendo.2024.1367229 · 被引用次数：20 · 研究领域：Congenital Anomalies and Fetal Surgery、Folate and B Vitamins Research、Genetic Associations and Epidemiology

Background General obesity is a well-established risk factor for gallstone disease (GSD), but whether central obesity contributes additional independent risk remains controversial. We aimed to comprehensively clarify the effect of body fat distribution on GSD. Methods We first investigated the observational association of central adiposity, characterized by waist-to-hip ratio (WHR), with GSD risk using data from UK Biobank (N=472,050). We then explored the genetic relationship using summary statistics from the largest genome-wide association study of GSD ( n case =43,639, n control =506,798) as well as WHR, with and without adjusting for body mass index (BMI) (WHR: n =697,734; WHR adj BMI: n =694,649). Results Observational analysis demonstrated an increased risk of GSD with one unit increase in WHR (HR=1.18, 95%CI=1.14-1.21). A positive WHR-GSD genetic correlation ( r g =0.41, P =1.42×10 -52 ) was observed, driven by yet independent of BMI (WHR adj BMI: r g =0.19, P =6.89×10 -16 ). Cross-trait meta-analysis identified four novel pleiotropic loci underlying WHR and GSD with biological mechanisms outside of BMI. Mendelian randomization confirmed a robust WHR-GSD causal relationship (OR=1.50, 95%CI=1.35-1.65) which attenuated yet remained significant after adjusting for BMI (OR=1.17, 95%CI=1.09-1.26). Furthermore, observational analysis confirmed a positive association between general obesity and GSD, corroborated by a shared genetic basis ( r g =0.40...