Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

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. © 2017 the authors.