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

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.