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BACKGROUND:Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. METHODS AND RESULTS:To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. CONCLUSIONS:Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.

Original publication

DOI

10.1161/jaha.116.004918

Type

Journal article

Journal

Journal of the American Heart Association

Publication Date

26/05/2017

Volume

6

Addresses

Framingham Heart Study, Framingham, MA ci.song@nih.gov.

Keywords

Humans, Coronary Disease, Genetic Predisposition to Disease, Blood Glucose, Lipoproteins, HDL, Plasminogen Activator Inhibitor 1, Incidence, Multivariate Analysis, Odds Ratio, Risk Assessment, Risk Factors, Fibrinolysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis, Biomarkers, Observational Studies as Topic