Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease

作者全名："Yan, Peijing; Zhang, Li; Yang, Chao; Zhang, Wenqiang; Wang, Yutong; Zhang, Min; Cui, Huijie; Tang, Mingshuang; Chen, Lin; Wu, Xueyao; Zhao, Xunying; Zou, Yanqiu; Xiao, Jinyu; Liu, Yunjie; Xiao, Chenghan; Yang, Yanfang; Zhang, Ling; Yao, Yuqin; Li, Jiayuan; Liu, Zhenmi; Yang, Chunxia; Jiang, Xia; Zhang, Ben"

作者地址："[Yan, Peijing; Zhang, Li; Yang, Chao; Zhang, Wenqiang; Wang, Yutong; Cui, Huijie; Tang, Mingshuang; Chen, Lin; Wu, Xueyao; Zhao, Xunying; Zou, Yanqiu; Xiao, Jinyu; Liu, Yunjie; Yang, Yanfang; Li, Jiayuan; Yang, Chunxia; Jiang, Xia; Zhang, Ben] Sichuan Univ, Inst Syst Epidemiol, Dept Epidemiol & Biostat, Chengdu, Sichuan, Peoples R China; [Yan, Peijing; Zhang, Li; Yang, Chao; Zhang, Wenqiang; Wang, Yutong; Cui, Huijie; Tang, Mingshuang; Chen, Lin; Wu, Xueyao; Zhao, Xunying; Zou, Yanqiu; Xiao, Jinyu; Liu, Yunjie; Yang, Yanfang; Li, Jiayuan; Yang, Chunxia; Jiang, Xia; Zhang, Ben] Sichuan Univ, West China Sch Publ Hlth, West China PUMC CC Chen Inst Hlth, Chengdu, Sichuan, Peoples R China; [Yan, Peijing; Zhang, Li; Yang, Chao; Zhang, Wenqiang; Wang, Yutong; Cui, Huijie; Tang, Mingshuang; Chen, Lin; Wu, Xueyao; Zhao, Xunying; Zou, Yanqiu; Xiao, Jinyu; Liu, Yunjie; Yang, Yanfang; Li, Jiayuan; Yang, Chunxia; Jiang, Xia; Zhang, Ben] Sichuan Univ, West China Hosp 4, Chengdu, Sichuan, Peoples R China; [Yang, Chao] Southwest Med Univ, Sch Publ Hlth, Luzhou, Sichuan, Peoples R China; [Zhang, Min] Chongqing Med Univ, Women & Childrens Hosp, Clin Res Ctr, Chongqing, Peoples R China; [Xiao, Chenghan; Liu, Zhenmi] Sichuan Univ, West China Sch Publ Hlth, Dept Maternal Child & Adolescent Hlth, Chengdu, Peoples R China; [Xiao, Chenghan; Yao, Yuqin; Liu, Zhenmi; Jiang, Xia; Zhang, Ben] Sichuan Univ, West China Hosp 4, Chengdu, Peoples R China; [Zhang, Ling] Sichuan Univ, Sch Polymer Sci & Engn, Dept Iatr Polymer Mat & Artificial Apparat, Chengdu, Peoples R China; [Yao, Yuqin; Zhang, Ben] Sichuan Univ, West China Sch Publ Hlth, Dept Occupat & Environm Hlth, Chengdu, Peoples R China; [Jiang, Xia] Sichuan Univ, Dept Nutr & Food Hyg, West China Sch Publ Hlth, Chengdu, Peoples R China; [Jiang, Xia] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden"

通信作者："Jiang, X; Zhang, B (通讯作者)，Sichuan Univ, Inst Syst Epidemiol, Dept Epidemiol & Biostat, Chengdu, Sichuan, Peoples R China.; Jiang, X; Zhang, B (通讯作者)，Sichuan Univ, West China Sch Publ Hlth, West China PUMC CC Chen Inst Hlth, Chengdu, Sichuan, Peoples R China.; Jiang, X; Zhang, B (通讯作者)，Sichuan Univ, West China Hosp 4, Chengdu, Sichuan, Peoples R China.; Jiang, X; Zhang, B (通讯作者)，Sichuan Univ, West China Hosp 4, Chengdu, Peoples R China.; Zhang, B (通讯作者)，Sichuan Univ, West China Sch Publ Hlth, Dept Occupat & Environm Hlth, Chengdu, Peoples R China.; Jiang, X (通讯作者)，Sichuan Univ, Dept Nutr & Food Hyg, West China Sch Publ Hlth, Chengdu, Peoples R China.; Jiang, X (通讯作者)，Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden."

来源：FRONTIERS IN ENDOCRINOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001161514200001

JCR分区：Q2

影响因子：5.2

年份：2024

卷号：14

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：type 2 diabetes mellitus; gallstone disease; Mendelian randomization; bidirectional; causal relationship; genetic association; cohort

摘要："<bold>Background:</bold> The relationship between type 2 diabetes mellitus (T2DM) and gallstone disease (GSD) have been incompletely understood. We aimed to investigate their phenotypic and genetic associations and evaluate the biological mechanisms underlying these associations. <bold>Methods:</bold> We first evaluated the phenotypic association between T2DM and GSD using data from the UK Biobank (n>450,000) using a prospective observational design. We then conducted genetic analyses using summary statistics from a meta-analysis of genome-wide association studies of T2DM, with and without adjusting for body mass index (BMI) (N-case=74,124, N-control=824,006; T2DM(adj)BMI: N-case=50,409, N-control=523,897) and GSD (N-case=43,639, N-control=506,798). <bold>Results:</bold> A unidirectional phenotypic association was observed, where individuals with T2DM exhibited a higher GSD risk (hazard ratio (HR)=1.39, P<0.001), but not in the reverse direction (GSD -> T2DM: HR=1.00, P=0.912). The positive T2DM-GSD genetic correlation (r(g)=0.35, P=7.71x10(-23)) remained even after adjusting for BMI (T2DM(adj)BMI: r(g)=0.22, P=4.48x10(-10)). Mendelian randomization analyses provided evidence of a unidirectional causal relationship (T2DM -> GSD: odds ratio (OR)=1.08, P=4.6x10(-8); GSD -> T2DM: OR=1.02, P=0.48), even after adjusting for important metabolic confounders (OR=1.02, P=0.02). This association was further corroborated through a comprehensive functional analysis reflected by 23 pleiotropic single nucleotide polymorphisms, as well as multiple neural and motor-enriched tissues. <bold>Conclusion:</bold> Through comprehensive observational and genetic analyses, our study clarified the causal relationship between T2DM and GSD, but not in the reverse direction. These findings might provide new insights into prevention and treatment strategies for T2DM and GSD."

基金机构：National Natural Science Foundation of China10.13039/501100001809

基金资助正文：We are grateful to all the investigators who shared genome-wide summary statistics.