期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 6, 期 6, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.116.004918
关键词
coronary heart disease; genome-wide association study; Mendelian randomization; plasminogen activator inhibitor type 1; single nucleotide polymorphism
资金
- NHLBI Intramural funds
- Wellcome Trust [100114]
- MRC [MR/L003120/1, MR/K013351/1, MC_UP_0801/1, MC_UU_00002/7] Funding Source: UKRI
- British Heart Foundation [RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [MC_UP_0801/1, MC_UU_00002/7, MR/K013351/1, MR/L003120/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10135, NF-SI-0512-10165] Funding Source: researchfish
- Wellcome Trust [204623/Z/16/Z] Funding Source: researchfish
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.
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