ArticleCardiovascular diabetology2026
Ancestry-specific genetics of amino acids and microbiota-related metabolites reveal causal effects on cardiometabolic disease in Chinese populations.
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50 authors.
Yilan Ding *Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Hong Lin *Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Yue Yin *Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Mian LiDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Yu XuDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Shuangyuan WangDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Min XuDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Jie ZhengDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Tiange WangDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Zhiyun ZhaoDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Xiadi HeDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Ruixin LiuDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Hong QiaoThe Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Guijun QinThe First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Yingfen QinThe First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Xulei TangThe First Hospital of Lanzhou University, Lanzhou, China.
Zhen YeZhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
Ruying HuZhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
Lixin ShiThe Affiliated Hospital of Guiyang Medical College, Guiyang, China.
Qing SuXinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Xuefeng YuTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Li YanSun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Qin WanThe Affiliated Hospital of Southwest Medical University, Luzhou, China.
Gang ChenFujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
Zhengnan GaoDalian Municipal Central Hospital, Dalian, China.
Guixia WangThe First Hospital of Jilin University, Changchun, China.
Feixia ShenThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Xuejiang GuThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Zuojie LuoThe First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Li ChenQilu Hospital of Shandong University, Jinan, China.
Xinguo HouQilu Hospital of Shandong University, Jinan, China.
Yanan HuoJiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China.
Qiang LiThe Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Yinfei ZhangCentral Hospital of Shanghai Jiading District, Shanghai, China.
Tianshu ZengUnion Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Chao LiuJiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China.
Youmin WangThe First Affiliated Hospital of Anhui Medical University, Hefei, China.
Shengli WuKaramay Municipal People's Hospital, Xinjiang, China.
Tao YangThe First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Huacong DengThe First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Donghui LiDepartment of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Shenghan LaiDepartment of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
Lulu ChenUnion Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jiajun ZhaoShandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
Yiming MuChinese People's Liberation Army General Hospital, Beijing, China.
Guang NingDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Weiqing WangDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. wqingw61@shsmu.edu.cn.
Yufang BiDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. byf10784@rjh.com.cn.
Jieli LuDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. ljl11319@rjh.com.cn.
4C Study Group
Funding
Ministry of Science and Technology of China grant no. 2022YFC2505202National Key Research and Development Program of China grant nos. 2025YFA1805800National Natural Science Foundation of China grant nos. 82370810, 91857205, 82372347 and 82200998Noncommunicable Chronic Diseases-National Science and Technology Major Project grant nos. 2023ZD0508402, 2023ZD0508401, 2023ZD0508403, 2023ZD0508901, 2023ZD0508902Science and Technology Committee of Shanghai grant nos. 22Y31900300, 23Y11908400 and 23JS1400900
Abstract
backgroundThe genetic architecture of circulating amino acids (AAs) and microbiota-related metabolites (MRMs) in relation to cardiometabolic disease remains poorly characterized in East Asian populations, limiting ancestry-specific insights.
methodsIn a prospective cohort of 2953 Chinese individuals, we performed a large-scale genome-wide association study (GWAS) of 28 serum AAs and 22 MRMs. We conducted a cross-ancestry comparison of variant-metabolite associations. Using colocalization and Mendelian randomization (MR), we further investigated causal roles of 50 AAs and MRMs in 25 cardiometabolic diseases from the BioBank Japan. Furthermore, we explored differences in the genetic regulation of these metabolites between incident T2DM cases and healthy controls.
resultsWe identified 33 metabolite-variant associations, 22 of which were previously unreported, and revealed several loci specific to East Asian ancestry. Integrative colocalization and MR analyses established 49 causal relationships between metabolite levels and cardiometabolic diseases, most notably implicating genetically predicted N-acetyltryptophan to increased risk of type 2 diabetes. Moreover, we observed distinct patterns of genetic regulation between T2DM cases and controls, highlighting substantial heterogeneity of effects and dynamic gene-disease interplay.
conclusionsThese findings offer crucial insights into the ancestry-specific genetic determinants of metabolic traits, and shed new light on their causal roles in the etiology of cardiometabolic diseases in East Asian populations.
Indexed as
Amino AcidsDiabetes Mellitus, Type 2Gastrointestinal MicrobiomePolymorphism, Single NucleotideAgedCardiometabolic Risk FactorsCase-Control StudiesChinaEast Asian PeopleFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansJapanMaleMendelian Randomization AnalysisAmino AcidsAmino acidsCardiometabolic diseaseGenome-wide association studyMicrobiota-related metabolites
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