Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease
Authors
Song, C
Eicher, JD
CHARGE Consortium Hemostatic Factor Working Group,
ICBP Consortium,
CHARGE Consortium Subclinical Working Group,
O’Donnell, CJ
Johnson, AD
Publication Date
2017-06Journal Title
Journal of the American Heart Association
ISSN
2047-9980
Publisher
Wiley
Volume
6
Issue
6
Number
e004918
Language
English
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Song, C., Burgess, S., Eicher, J., CHARGE Consortium Hemostatic Factor Working Group,, ICBP Consortium,, CHARGE Consortium Subclinical Working Group,, O’Donnell, C., & et al. (2017). Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease. Journal of the American Heart Association, 6 (6. e004918)https://doi.org/10.1161/JAHA.116.004918
Abstract
$\textit{Background—}$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.
$\textit{Methods and Results—}$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.
$\textit{Conclusions—}$Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.
Keywords
coronary heart disease, plasminogen activator inhibitor type 1, Mendelian randomization, genome-wide association study, single nucleotide polymorphism
Sponsorship
This work was supported by NHLBI Intramural funds to Christopher O’Donnell and Andrew Johnson. Stephen Burgess is supported by a fellowship from the Wellcome Trust (100114).
Funder references
Wellcome Trust (204623/Z/16/Z)
MRC (MR/L003120/1)
Wellcome Trust (100114/Z/12/Z)
British Heart Foundation (RG/08/014/24067)
Medical Research Council (MC_UU_00002/7)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1161/JAHA.116.004918
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264186
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International