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Causal associations of insulin resistance with coronary artery disease and ischemic stroke: a Mendelian randomization analysis.

ABSTRACT: INTRODUCTION: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. RESEARCH DESIGN AND METHODS: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. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Chen W

PROVIDER: S-EPMC7223029 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Causal associations of insulin resistance with coronary artery disease and ischemic stroke: a Mendelian randomization analysis.

Chen Weiqi W Wang Shukun S Lv Wei W Pan Yuesong Y

BMJ open diabetes research & care 20200501 1

<h4>Introduction</h4>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.<h4>Research design and methods</h4>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 polymorphism ...[more]

PMID: 32398352

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Project description:Background and purposePrevious studies have found ischemic stroke is associated with atrial fibrillation. However, the causal association between ischemic stroke and atrial fibrillation is not clear. Furthermore, the network relationship among ischemic stroke, atrial fibrillation and its risk factors need further attention. This study aims to examine the potential causal association between ischemic stroke and atrial fibrillation and further to explore potential mediators in the causal pathway from ischemic stroke to atrial fibrillation.MethodsSummary statistics from the ISGC (case = 10,307 and control = 19,326) were used as ischemic stroke genetic instruments, AFGen Consortium data (case = 65,446 and control = 522,744) were used for atrial fibrillation, and other consortia data were used for potential mediators (fasting insulin, white blood cell count, procalcitonin, systolic and diastolic blood pressure, body mass index, waist circumference, and height). Under the framework of network Mendelian randomization, two-sample Mendelian randomization study was performed using summary statistics from several genome-wide association studies. Inverse-variance weighted method was performed to estimate causal effect.ResultsBlood pressure mediates the causal pathways from ischemic stroke to atrial fibrillation. The total odds ratio of ischemic stroke on atrial fibrillation was 1.05 (95% confidence interval [CI], 1.02 to 1.07; P = 1.3 × 10-5). One-unit increase of genetically determined ischemic stroke was associated with 0.02 (DBP: 95% CI, 0.001 to 0.034, P = 0.029; SBP: 95% CI, 0.006 to 0.034, P = 0.003) upper systolic and diastolic blood pressure levels. Higher genetically determined systolic and diastolic blood pressure levels were associated with higher atrial fibrillation risk (DBP: RR, 1.18; 95% CI, 1.03 to 1.35; P = 0.012. SBP: RR, 1.18; 95% CI, 1.01 to 1.38; P = 0.04). Specially, we also found the bidirectional causality between blood pressure and ischemic stroke.ConclusionsOur study provided a strong evidence that raised blood pressure in stroke patients increases the risk of atrial fibrillation and active acute blood pressure lowering can improve the outcome in ischemic stroke patients.

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Dataset Information

Causal associations of insulin resistance with coronary artery disease and ischemic stroke: a Mendelian randomization analysis.

Publications

Causal associations of insulin resistance with coronary artery disease and ischemic stroke: a Mendelian randomization analysis.

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