Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease.
journal contributionposted on 26.04.2018, 14:13 by Ci Song, Stephen Burgess, John D. Eicher, Christopher J. O'Donnell, Andrew D. Johnson, Alison Goodall
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.
CitationJournal of the American Heart Association, 2017, 6, e004918
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences
VersionVoR (Version of Record)
Published inJournal of the American Heart Association
PublisherWiley Open Access
Mendelian randomizationcoronary heart diseasegenome‐wide association studyplasminogen activator inhibitor type 1single nucleotide polymorphismBiomarkersBlood GlucoseCoronary DiseaseFibrinolysisGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansIncidenceLipoproteins, HDLMendelian Randomization AnalysisMultivariate AnalysisObservational Studies as TopicOdds RatioPlasminogen Activator Inhibitor 1Polymorphism, Single NucleotideRisk AssessmentRisk Factors