Song Ci, Burgess Stephen, Eicher John D, O'Donnell Christopher J, Johnson Andrew D
Framingham Heart Study, Framingham, MA
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD.
J Am Heart Assoc. 2017 May 26;6(6):e004918. 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.
1型纤溶酶原激活物抑制剂（PAI-1）在纤维蛋白溶解系统和血栓形成中起重要作用。人群研究报告称，血液PAI-1水平与冠心病（CHD）风险增加相关。然而，尚不清楚这种关联是否反映了PAI-1对冠心病风险的因果影响。
为评估PAI-1与冠心病之间的关联，我们采用了三步策略。首先，我们通过基于对PAI-1和冠心病研究的文献检索进行系统评价，调查PAI-1与冠心病发病率之间的观察性关联。其次，我们使用孟德尔随机化方法，利用来自大型全基因组关联研究的汇总统计数据，探索PAI-1与冠心病之间的因果关联。最后，我们探讨了PAI-1对包括代谢和亚临床动脉粥样硬化指标在内的心血管危险因素的因果效应。在系统荟萃分析中，在年龄和性别调整模型中，血液PAI-1水平的最高分位数与最低分位数相比，冠心病风险更高（优势比=2.17；95%可信区间：1.53，3.07）。在使用多变量调整模型的研究中，效应大小有所降低（优势比=1.46；95%可信区间：1.13，1.88）。孟德尔随机化分析表明，PAI-1水平升高对冠心病风险有因果效应（对数转换后的PAI-1每增加一个单位，优势比=1.22；95%可信区间：1.01，1.47）。此外，我们还检测到PAI-1对血糖升高和高密度脂蛋白胆固醇有因果效应。
我们的研究表明，PAI-1水平升高对冠心病风险有因果效应，这可能由葡萄糖功能障碍介导。
