Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

نویسندگان

  • 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 Truong
  • Josyf 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
  • Joshua C. Bis
  • Barbara McKnight
  • John Öhrvik
  • Kent Taylor
  • Maria Grazia Franzosi
  • Udo Seedorf
  • Rory Collins
  • Anders Franco‐Cereceda
  • Ann‐Christine Syvänen
  • Alison H. Goodall
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  • Mary Cushman
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چکیده

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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عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2017