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.
Bibliographical noteFunding Information:
We thank the genetic consortia that provided the summarized statistics in this study, including CHARGE Hemostatic Working group for PAI-1, CARDIOGRAMplusC4D for CHD; DIAGRAM for T2D; MAGIC for blood glucose and insulin; GLGC for blood lipids; ICBP for blood pressure; GIANT for BMI and waist-hip ratio; CHARGE Subclinical Working group for IMT, carotid plaque and CAC. This work was supported by NHLBI Intramural funds to O'Donnell and Johnson. Stephen Burgess is supported by a fellowship from the Wellcome Trust (100114).
- Coronary heart disease
- Genome-wide association study
- Mendelian randomization
- Plasminogen activator inhibitor type 1
- Single nucleotide polymorphism