Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

• Published in: Journal of the American Heart Association Vol. 6; no. 6
• Main Authors: Song, Ci, Burgess, Stephen, Eicher, John D, O'Donnell, Christopher J, Johnson, Andrew D
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 26.05.2017; Wiley
• Subjects: Biomarkers - blood; Blood Glucose - metabolism; Coronary Disease - blood; Coronary Disease - diagnosis; Coronary Disease - epidemiology; Coronary Disease - genetics; coronary heart disease; Fibrinolysis - genetics; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Incidence; Lipoproteins, HDL - blood; Mendelian randomization; Mendelian Randomization Analysis; Multivariate Analysis; Observational Studies as Topic; Odds Ratio; Plasminogen Activator Inhibitor 1 - blood; Plasminogen Activator Inhibitor 1 - genetics; plasminogen activator inhibitor type 1; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; single nucleotide polymorphism; Systematic Review and Meta‐Analysis; coronary heart disease; Mendelian randomization; genome‐wide association study; single nucleotide polymorphism; plasminogen activator inhibitor type 1
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.116.004918

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. 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. Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.