Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, CHARGE Consortium Subclinical Working Group

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere004918
JournalJournal of the American Heart Association
Volume6
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Plasminogen Activator Inhibitor 1
Coronary Disease
Odds Ratio
Mendelian Randomization Analysis
Genome-Wide Association Study
Fibrinolysis
Random Allocation
HDL Cholesterol
Blood Glucose
Meta-Analysis
Atherosclerosis
Thrombosis

Keywords

  • Coronary heart disease
  • Genome-wide association study
  • Mendelian randomization
  • Plasminogen activator inhibitor type 1
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, & CHARGE Consortium Subclinical Working Group (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

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease. / CHARGE Consortium Hemostatic Factor Working Group; ICBP Consortium; CHARGE Consortium Subclinical Working Group.

In: Journal of the American Heart Association, Vol. 6, No. 6, e004918, 01.06.2017.

Research output: Contribution to journalArticle

CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium & CHARGE Consortium Subclinical Working Group 2017, 'Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease', Journal of the American Heart Association, vol. 6, no. 6, e004918. https://doi.org/10.1161/JAHA.116.004918
CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, CHARGE Consortium Subclinical Working Group. Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease. Journal of the American Heart Association. 2017 Jun 1;6(6). e004918. https://doi.org/10.1161/JAHA.116.004918
CHARGE Consortium Hemostatic Factor Working Group ; ICBP Consortium ; CHARGE Consortium Subclinical Working Group. / Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease. In: Journal of the American Heart Association. 2017 ; Vol. 6, No. 6.
@article{6aee102e135740ad81be93d725448cbc,
title = "Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease",
abstract = "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.",
keywords = "Coronary heart disease, Genome-wide association study, Mendelian randomization, Plasminogen activator inhibitor type 1, Single nucleotide polymorphism",
author = "{CHARGE Consortium Hemostatic Factor Working Group} and {ICBP Consortium} and {CHARGE Consortium Subclinical Working Group} and Ci Song and Stephen Burgess and Eicher, {John D.} and O'Donnell, {Christopher J.} and Johnson, {Andrew D.} and Jie Huang and Maria Sabater-Lleal and Asselbergs, {Folkert W.} and David Tregouet and Shin, {So Youn} and Jingzhong Ding and Jens Baumert and Tiphaine Oudot-Mellakh and Lasse Folkersen and Smith, {Nicholas L.} and Williams, {Scott M.} and Ikram, {Mohammad A.} and Kleber, {Marcus E.} and Becker, {Diane M.} and Vinh Truong and Mychaleckyj, {Josyf C.} and Weihong Tang and Qiong Yang and Bengt Sennblad and Moore, {Jason H.} and Williams, {Frances M.K.} and Abbas Dehghan and G{\"u}nther Silbernagel and Schrijvers, {Elisabeth M.C.} and Shelly Smith and Mahir Karakas and Tofler, {Geoffrey H.} and Angela Silveira and Navis, {Gerjan J.} and Kurt Lohman and Chen, {Ming Huei} and Annette Peters and Anuj Goel and Hopewell, {Jemma C.} and Chambers, {John C.} and Danish Saleheen and Per Lundmark and Psaty, {Bruce M.} and Strawbridge, {Rona J.} and Boehm, {Bernhard O.} and Carter, {Angela M.} and Christa Meisinger and Yanbin Dong and Xiaoling Wang and Haidong Zhu",
year = "2017",
month = "6",
day = "1",
doi = "10.1161/JAHA.116.004918",
language = "English (US)",
volume = "6",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

AU - CHARGE Consortium Hemostatic Factor Working Group

AU - ICBP Consortium

AU - CHARGE Consortium Subclinical Working Group

AU - Song, Ci

AU - Burgess, Stephen

AU - Eicher, John D.

AU - O'Donnell, Christopher J.

AU - Johnson, Andrew D.

AU - Huang, Jie

AU - Sabater-Lleal, Maria

AU - Asselbergs, Folkert W.

AU - Tregouet, David

AU - Shin, So Youn

AU - Ding, Jingzhong

AU - Baumert, Jens

AU - Oudot-Mellakh, Tiphaine

AU - Folkersen, Lasse

AU - Smith, Nicholas L.

AU - Williams, Scott M.

AU - Ikram, Mohammad A.

AU - Kleber, Marcus E.

AU - Becker, Diane M.

AU - Truong, Vinh

AU - Mychaleckyj, Josyf C.

AU - Tang, Weihong

AU - Yang, Qiong

AU - Sennblad, Bengt

AU - Moore, Jason H.

AU - Williams, Frances M.K.

AU - Dehghan, Abbas

AU - Silbernagel, Günther

AU - Schrijvers, Elisabeth M.C.

AU - Smith, Shelly

AU - Karakas, Mahir

AU - Tofler, Geoffrey H.

AU - Silveira, Angela

AU - Navis, Gerjan J.

AU - Lohman, Kurt

AU - Chen, Ming Huei

AU - Peters, Annette

AU - Goel, Anuj

AU - Hopewell, Jemma C.

AU - Chambers, John C.

AU - Saleheen, Danish

AU - Lundmark, Per

AU - Psaty, Bruce M.

AU - Strawbridge, Rona J.

AU - Boehm, Bernhard O.

AU - Carter, Angela M.

AU - Meisinger, Christa

AU - Dong, Yanbin

AU - Wang, Xiaoling

AU - Zhu, Haidong

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

KW - Coronary heart disease

KW - Genome-wide association study

KW - Mendelian randomization

KW - Plasminogen activator inhibitor type 1

KW - Single nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85020419920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020419920&partnerID=8YFLogxK

U2 - 10.1161/JAHA.116.004918

DO - 10.1161/JAHA.116.004918

M3 - Article

C2 - 28550093

AN - SCOPUS:85020419920

VL - 6

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 6

M1 - e004918

ER -