American Diabetes Association
DB22-0954R3-Supplementary Materials[AU].pdf (3.29 MB)

Additional Evidence for the Relationship between Type 2 Diabetes Mellitus and Stroke through Observational and Genetic Analyses

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Version 2 2023-08-24, 13:59
Version 1 2023-08-08, 20:46
posted on 2023-08-24, 13:59 authored by Wenqiang Zhang, Li Zhang, Jingwei Zhu, Chenghan Xiao, Huijie Cui, Chao Yang, Peijing Yan, Mingshuang Tang, Yutong Wang, Lin Chen, Yunjie Liu, Yanqiu Zou, Xueyao Wu, Ling Zhang, Chunxia Yang, Yuqin Yao, Jiayuan Li, Zhenmi Liu, Xia Jiang, Ben Zhang

While type 2 diabetes mellitus (T2DM) is commonly considered a putative causal risk factor for stroke, the effect of stroke on T2DM remains unclear. The intrinsic link underlying T2DM and stroke has neither been thoroughly examined. We aimed to evaluate the phenotypic and genetic relationships underlying T2DM and stroke. We evaluated phenotypic associations using data from the UK Biobank (N=472,050). We then investigated genetic relationships leveraging genomic data in European ancestry for T2DM, with and without adjusting for body mass index (BMI) (T2DM: Ncase/Ncontrol=74,124/824,006; T2DMadjBMI: Ncase/Ncontrol=50,409/523,897), and for stroke (Ncase/Ncontrol=73,652/1,234,808). We performed additional analyses using genomic data in East Asian ancestry for T2DM (Ncase/Ncontrol=77,418/356,122) and for stroke (Ncase/Ncontrol=27,413/237,242). Observational analyses suggested a significantly increased hazard of stroke among individuals with T2DM (hazard ratio 2.28 [95%CI 1.97, 2.64]), but a slightly increased hazard of T2DM among individuals with stroke (1.22 [1.03, 1.45]) which attenuated to 1.14 [0.96, 1.36] in sensitivity analysis. A positive global T2DM-stroke genetic correlation was observed (rg=0.35; P=1.46×10-27), largely independent of BMI (T2DMadjBMI-stroke: rg=0.27; P=3.59×10-13). This was further corroborated by 38 shared independent loci and 161 shared expression-trait associations. Mendelian randomization analyses suggested a putative causal effect of T2DM on stroke in Europeans (odds ratio 1.07 [95%CI 1.06, 1.09]), which remained significant in East Asians (1.03 [1.01, 1.06]). Conversely, despite a putative causal effect of stroke on T2DM also observed in Europeans (1.21 [1.07, 1.37]), it attenuated to 1.04 [0.91, 1.19] in East Asians. Our study provides additional evidence to underscore the significant relationship between T2DM and stroke.


This study was supported by the National Key R&D Program of China (2022YFC3600600, 2022YFC3600604), the National Natural Science Foundation of China (U22A20359, 81874283, 81673255), the Recruitment Program for Young Professionals of China, the Promotion Plan for Basic Medical Sciences and the Development Plan for Cutting-Edge Disciplines, Sichuan University, and other Projects from West China School of Public Health and West China Fourth Hospital, Sichuan University. The sponsors of this study had no role in study design, data collection, analysis, interpretation, writing of the report, or the decision for submission.


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