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 - Rao, Dabeeru C.
AU - Kraja, Aldi T.
AU - Province, Michael A.
N1 - Publisher Copyright:
© 2017 The Authors.
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
U2 - 10.1161/JAHA.116.004918
DO - 10.1161/JAHA.116.004918
M3 - Article
C2 - 28550093
AN - SCOPUS:85020419920
SN - 2047-9980
VL - 6
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 6
M1 - e004918
ER -