Chen Weiqi, Wang Shukun, Lv Wei, Pan Yuesong
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
BMJ Open Diabetes Res Care. 2020 May;8(1). doi: 10.1136/bmjdrc-2020-001217.
The relationship between insulin resistance (IR) and cardiovascular diseases is unclear. We aimed to examine the causal associations of IR with cardiovascular diseases, including coronary artery disease, myocardial infarction, ischemic stroke and its subtypes, using Mendelian randomization.
Due to low sample size for gold standard measures and in order to well reflect the underlying phenotype of IR, we used 53 single nucleotide polymorphisms associated with IR phenotypes (ie, fasting insulin, high-density lipoprotein cholesterol and triglycerides) from recent genome-wide association studies (GWASs) as instrumental variables. Summary-level data from four GWASs of European individuals were used. Data on IR phenotypes were obtained from meta-analysis of GWASs of up to 188 577 individuals and data on the outcomes from GWASs of up to 446 696 individuals. Mendelian randomization (MR) estimates were calculated with inverse-variance weighted, simple and weighted-median approaches and MR-Egger regression was used to explore pleiotropy.
Genetically predicted 1-SD increase in IR phenotypes were associated with a substantial increase in risk of coronary artery disease (OR=1.79, 95% CI: 1.57 to 2.04, p<0.001), myocardial infarction (OR=1.78, 95% CI: 1.54 to 2.06, p<0.001), ischemic stroke (OR=1.21, 95% CI: 1.05 to 1.40, p=0.007) and the small-artery occlusion subtype of stroke (OR=1.80, 95% CI: 1.30 to 2.49, p<0.001), but not associated with the large-artery atherosclerosis and cardioembolism subtypes of stroke. There was no evidence of pleiotropy. Results were broadly consistent in sensitivity analyses using simple and weighted-median approaches accounting for potential genetic pleiotropy.
This study provides evidence to support that IR was causally associated with risk of coronary artery disease, myocardial infarction, ischemic stroke and the small-artery occlusion subtype of stroke.
胰岛素抵抗（IR）与心血管疾病之间的关系尚不清楚。我们旨在利用孟德尔随机化方法研究IR与心血管疾病（包括冠状动脉疾病、心肌梗死、缺血性中风及其亚型）之间的因果关联。
由于金标准测量的样本量较小，且为了更好地反映IR的潜在表型，我们使用了来自近期全基因组关联研究（GWAS）的53个与IR表型（即空腹胰岛素、高密度脂蛋白胆固醇和甘油三酯）相关的单核苷酸多态性作为工具变量。使用了四项欧洲个体GWAS的汇总数据。IR表型数据来自对多达188577名个体的GWAS荟萃分析，结局数据来自对多达446696名个体的GWAS。采用逆方差加权、简单和加权中位数方法计算孟德尔随机化（MR）估计值，并使用MR-Egger回归探索多效性。
遗传预测的IR表型增加1个标准差与冠状动脉疾病风险大幅增加相关（OR=1.79，95%CI：1.57至2.04，p<0.001）、心肌梗死（OR=1.78，95%CI：1.54至2.06，p<0.001）、缺血性中风（OR=1.21，95%CI：1.05至1.40，p=0.007）以及中风的小动脉闭塞亚型（OR=1.80，95%CI：1.30至2.49，p<0.001），但与中风的大动脉粥样硬化和心源性栓塞亚型无关。没有多效性的证据。在使用考虑潜在基因多效性的简单和加权中位数方法进行的敏感性分析中，结果大致一致。
本研究提供了证据支持IR与冠状动脉疾病、心肌梗死、缺血性中风以及中风的小动脉闭塞亚型的风险存在因果关联。
