학술논문
Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease
Document Type
article
Author
Song, Ci; Burgess, Stephen; Eicher, John D; O'Donnell, Christopher J; Johnson, Andrew D; Huang, Jie; Sabater‐Lleal, Maria; Asselbergs, Folkert W; Tregouet, David; Shin, So‐Youn; Ding, Jingzhong; Baumert, Jens; Oudot‐Mellakh, Tiphaine; Folkersen, Lasse; Smith, Nicholas L; Williams, Scott M; Ikram, Mohammad A; Kleber, Marcus E; Becker, Diane M; Truong, Vinh; Mychaleckyj, Josyf C; Tang, Weihong; Yang, Qiong; Sennblad, Bengt; Moore, Jason H; Williams, Frances MK; Dehghan, Abbas; Silbernagel, Günther; Schrijvers, Elisabeth MC; Smith, Shelly; Karakas, Mahir; Tofler, Geoffrey H; Silveira, Angela; Navis, Gerjan J; Lohman, Kurt; Chen, Ming‐Huei; Peters, Annette; Goel, Anuj; Hopewell, Jemma C; Chambers, John C; Saleheen, Danish; Lundmark, Per; Psaty, Bruce M; Strawbridge, Rona J; Boehm, Bernhard O; Carter, Angela M; Meisinger, Christa; Peden, John F; Bis, Joshua C; McKnight, Barbara; Öhrvik, John; Taylor, Kent; Franzosi, Maria Grazia; Seedorf, Udo; Collins, Rory; Franco‐Cereceda, Anders; Syvänen, Ann‐Christine; Goodall, Alison H; Yanek, Lisa R; Cushman, Mary; Müller‐Nurasyid, Martina; Folsom, Aaron R; Basu, Saonli; Matijevic, Nena; van Gilst, Wiek H; Kooner, Jaspal S; Hofman, Albert; Danesh, John; Clarke, Robert; Meigs, James B; Kathiresan, Sekar; Reilly, Muredach P; Klopp, Norman; Harris, Tamara B; Winkelmann, Bernhard R; Grant, Peter J; Hillege, Hans L; Watkins, Hugh; Spector, Timothy D; Becker, Lewis C; Tracy, Russell P; März, Winfried; Uitterlinden, Andre G; Eriksson, Per; Cambien, Francois; Morange, Pierre‐Emmanuel; Koenig, Wolfgang; Soranzo, Nicole; van der Harst, Pim; Liu, Yongmei; Hamsten, Anders; Ehret, Georg B; Munroe, Patricia B; Rice, Kenneth M; Bochud, Murielle; Chasman, Daniel I; Smith, Albert V; Tobin, Martin D; Verwoert, Germaine C
Source
Journal of the American Heart Association. 6(6)
Subject
Language
Abstract
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. 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. Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.