Article Text
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.
- insulin resistance
- stroke
- coronary artery disease
- genetics
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Footnotes
WC and SW contributed equally.
Contributors WC and YP designed the study and drafted the manuscript. SW, WL and YP collected the data. WC and YP performed the analysis and interpreted the data.
Funding This work was supported by grants from the National Natural Science Foundation of China (81971091, 81901177), Beijing Hospitals Authority Youth Programme (QML20190501), Ministry of Science and Technology of the People’s Republic of China (2016YFC0901002, 2016YFC0901001, 2017YFC1310901, 2017YFC1310902, 2017YFC1307905, 2018YFC1311700 and 2018YFC1311706), Beijing Municipal Administration of Hospitals (SML20150502), Beijing Municipal Science & Technology Commission (D171100003017002, D151100002015003), National Science and Technology Major Project (2017ZX09304018) and Beijing Tiantan Hospital (2018-YQN-1). The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The protocol and data collection were approved by the ethics committee of the original GWAS study sites.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. There are no additional, unpublished data available from this study.