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

Ci Song, Stephen Burgess, John D. Eicher, Christopher J. O'Donnell, Andrew D. Johnson, Jie Huang, Maria Sabater-Lleal, Folkert W. Asselbergs, David Tregouet, So Youn Shin, Jingzhong Ding, Jens Baumert, Tiphaine Oudot-Mellakh, Lasse Folkersen, Nicholas L. Smith, Scott M. Williams, Mohammad A. Ikram, Marcus E. Kleber, Diane M. Becker, Vinh TruongJosyf C. Mychaleckyj, Weihong Tang, Qiong Yang, Bengt Sennblad, Jason H. Moore, Frances M.K. Williams, Abbas Dehghan, Günther Silbernagel, Elisabeth M.C. Schrijvers, Shelly Smith, Mahir Karakas, Geoffrey H. Tofler, Angela Silveira, Gerjan J. Navis, Kurt Lohman, Ming Huei Chen, Annette Peters, Anuj Goel, Jemma C. Hopewell, John C. Chambers, Danish Saleheen, Per Lundmark, Bruce M. Psaty, Rona J. Strawbridge, Bernhard O. Boehm, Angela M. Carter, Christa Meisinger, John F. Peden, Aaron R. Folsom, Saonli Basu, CHARGE Consortium Hemostatic Factor Working Group, ICBP Consortium, CHARGE Consortium Subclinical Working Group

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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

Bibliographical note

Funding Information:
We thank the genetic consortia that provided the summarized statistics in this study, including CHARGE Hemostatic Working group for PAI-1, CARDIOGRAMplusC4D for CHD; DIAGRAM for T2D; MAGIC for blood glucose and insulin; GLGC for blood lipids; ICBP for blood pressure; GIANT for BMI and waist-hip ratio; CHARGE Subclinical Working group for IMT, carotid plaque and CAC. This work was supported by NHLBI Intramural funds to O'Donnell and Johnson. Stephen Burgess is supported by a fellowship from the Wellcome Trust (100114).

Keywords

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

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