孟德尔随机化
胰岛素抵抗
优势比
内科学
非酒精性脂肪肝
全基因组关联研究
肌萎缩
疾病
2型糖尿病
医学
生物
糖尿病
胰岛素
内分泌学
脂肪肝
遗传学
单核苷酸多态性
遗传变异
基因型
基因
作者
Chaojie Ye,Lijie Kong,Yiying Wang,Jie Zheng,Mingqing Xu,Yu Xu,Mian Li,Zhiyun Zhao,Jieli Lu,Yuhong Chen,Weiqing Wang,Guang Ning,Jie Zheng,Tiange Wang
出处
期刊:Aging Cell
[Wiley]
日期:2023-07-05
卷期号:22 (9)
被引量:8
摘要
The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10-1.32] for ALM to 2.30 [1.14-4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08-1.64] for ALM to 2.30 [1.02-5.18] for grip strength), hypertension (1.12 [1.05-1.20] for ALM to 4.43 [2.68-7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13-1.27] for ALM to 2.73 [1.84-4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11-1.25] for ALM to 2.47 [1.63-3.73] for walking pace), small vessel stroke (1.25 [1.15-1.37] for ALM to 1.29 [1.10-1.52] for WBLM), and Alzheimer's disease (1.10 [1.05-1.15] for ALM to 1.28 [1.19-1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%-34% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk.
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