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

Authors: Ci Song, Stephen Burgess, John D. Eicher, Christopher J. O’Donnell, Andrew D. Johnson, Jie Huang, Maria Sabater‐Lleal, Folkert W. Asselbergs, David‐Alexandre Trégouët, So‐Youn Shin, Jingzhong Ding, Jens Baumert, Tiphaine Oudot‐Mellakh, Lasse Folkersen, Nicholas L. Smith, Scott M. Williams, M. Arfan Ikram, Marcus E. Kleber, Diane M. Becker, Vinh Trương, Josyf C. Mychaleckyj, Weihong Tang, Qiong Yang, Bengt Sennblad, Jason H. Moore, Frances M. K. Williams, Abbas Dehghan, Günther Silbernagel, Elisabeth M. C. Schrijvers, S. Carrie Smith, Mahir Karakas, Geoffrey H. Tofler, Angela Silveira, Gerjan 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 D. Taylor, Maria Grazia Franzosi, Udo Seedorf, Rory Collins, Anders Franco‐Cereceda, Ann‐Christine Syvänen, Alison H. Goodall, Lisa R. Yanek, Mary Cushman, Martina Müller‐Nurasyid, Aaron R. Folsom, Saonli Basu, Nena Matijevic, Wiek H. van Gilst, Jaspal S. Kooner, Albert Hofman, John Danesh, Robert W. Clarke, James B. Meigs, Sekar Kathiresan, Muredach P. Reilly, Norman Klopp, Tamara B. Harris, Bernhard R. Winkelmann, Peter J. Grant, Hans L. Hillege, Hugh Watkins, Timothy D. Spector, Lewis C. Becker, Russell P. Tracy, Winfried März, André G. Uitterlinden, Per Eriksson, François Cambien, Pierre‐Emmanuel Morange, Wolfgang Köenig, Nicole Soranzo, Pim van der Harst, Ching‐Ti Liu, Anders Hamsten, Georg Ehret, Patricia B. Munroe, Kenneth Rice, Murielle Bochud, Andrew D. Johnson, Daniel I. Chasman, Albert V. Smith, Martin D. Tobin, Germaine C. Verwoert, Shih‐Jen Hwang, Vasyl Pihur, Péter Vollenweider, Paul F. O’Reilly, Najaf Amin, Jennifer L. Bragg‐Gresham, Alexander Teumer, Nicole L. Glazer, Lenore Launer, Jing Zhao, Yurii S. Aulchenko, Simon Heath, Siim Sõber, Afshin Parsa, Jian’an Luan, Pankaj Arora, Abbas Dehghan, Feng Zhang, Gavin Lucas, Andrew A. Hicks, Anne Jackson, John F. Peden, Toshiko Tanaka, Sarah H. Wild, Igor Rudan, Wilmar Igl, Yuri Milaneschi, Alex Parker, Cristiano Fava, John C. Chambers, Ervin R. Fox, Meena Kumari, Min Jin Go, Pim van der Harst, Wen Hong Linda Kao, Marketa Sjögren, D. G. Vinay, M Alexander, Yasuharu Tabara, Sue Shaw‐Hawkins, Peter H. Whincup, Ching‐Ti Liu, Gang Shi, Johanna Kuusisto, Bamidele O. Tayo, Mark Seielstad, Xueling Sim, Khanh‐Dung Hoang Nguyen, Terho Lehtimäki, Giuseppe Matullo, Ying Wu, Tom R. Gaunt, N. Charlotte Onland‐Moret, Matthew N. Cooper, Carl G. P. Platou, Elin Org, Rebecca Hardy, Santosh Dahgam, Jutta Palmen, Véronique Vitart, Peter S. Braund, Tatiana Kuznetsova, Cuno S.P.M. Uiterwaal, Adebowale Adeyemo, Walter Palmas, Harry Campbell, Barbara Ludwig, Maciej Tomaszewski, Ioanna Tzoulaki, Nicholette D. Palmer, Thor Aspelund, Melissa Garcia, Yen‐Pei C. Chang, Jeffrey R. O’Connell, Nanette Steinle, Diederick E. Grobbee, Dan E. Arking, Sharon L. R. Kardia, Alanna C. Morrison, Dena Hernández, Samer F. Najjar, Wendy L. McArdle, David Hadley, Morris J. Brown, John Connell, Aroon D. Hingorani, Ian N. M. Day, Debbie A. Lawlor, John Beilby, Robert Lawrence, Robert W. Clarke, Jemma C. Hopewell, Halit Ongen, Albert W. Dreisbach, Yali Li, J. Hunter Young, Joshua C. Bis, Mika Kähönen, Jorma Viikari, Linda S. Adair, Sang Lee, Ming‐Huei Chen, Matthias Olden, Cristian Pattaro, Judith A. Hoffman Bolton, Anna Köttgen, Sven Bergmann, Vincent Mooser, Nish Chaturvedi, Timothy M. Frayling, Muhammad Shariful Islam, Tazeen H. Jafar, Jeanette Erdmann, Smita Kulkarni, Stefan R. Bornstein, Jürgen Gräßler, Leif Groop, Benjamin F. Voight, Johannes Kettunen, Philip Howard, Andrew M. Taylor, Simonetta Guarrera, Fulvio Ricceri, Valur Emilsson, Andrew Plump, Inês Barroso, Kay‐Tee Khaw, Alan B. Weder, Steven C. Hunt, Yan V. Sun, Richard N. Bergman, Francis S. Collins, Lori L. Bonnycastle, Laura J. Scott, Heather M. Stringham, Leena Peltonen, Markus Perola, Erkki Vartiainen, Stefan‐Martin Brand, Jan A. Staessen, Thomas J. Wang, Paul R. Burton, María Soler Artigas, Yanbin Dong, Harold Snieder, Xiaoling Wang, Hai‐Dong Zhu, Kurt K. Lohman, Megan E. Rudock, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Ayo P. Doumatey, Daniel Shriner, Gudrun Veldre, Margus Viigimaa, Sanjay Kinra, Dorairaj Prabhakaran, Vikal Tripathy, Carl D. Langefeld, Annika Rosengren, Dag S. Thelle, A. Corsi, Andrew B. Singleton, Terrence Forrester, Gina M. Hilton, Colin A. McKenzie, Tunde Salako, Naoharu Iwai, Yoshikuni Kita, Toshio Ogihara, Takayoshi Ohkubo, Tomonori Okamura, Hirotsugu Ueshima, Satoshi Umemura, S. Eyheramendy, Thomas Meitinger, H.‐Erich Wichmann, Yoon Shin Cho, Hyung‐Lae Kim, Jong‐Young Lee, James Scott, Joban Sehmi, Weihua Zhang, Bo Hedblad, Peter Nilsson, George Davey Smith, Andrew S. Wong, Narisu Narisu, Alena Stančáková, Leslie J. Raffel, Jie Yao, Sekar Kathiresan, Stephen M. Schwartz, M. Arfan Ikram, W. T. Longstreth, Thomas H. Mosley, Sudha Seshadri, Nick Shrine, Louise V. Wain, Mario A. Morken, Amy J. Swift, Jaana Laitinen, Inga Prokopenko, Paavo Zitting, Jackie A. Cooper, Steve E. Humphries, John Danesh, Asif Rasheed, Anuj Goel, Anders Hamsten, Hugh Watkins, Stephan J. L. Bakker, Wiek H. van Gilst, Charles S. Janipalli, K. Radha Mani, Chittaranjan S. Yajnik, Albert Hofman, Francesco Mattace‐Raso, Ben A. Oostra, Ayşe Demirkan, Aaron Isaacs, Fernando Rivadeneira, Edward G. Lakatta, Marco Orrù, Angelo Scuteri, Mika Ala‐Korpela, Antti J. Kangas, Leo‐Pekka Lyytikäinen, Pasi Soininen, Taru Tukiainen, Peter Würtz, Rick Twee‐Hee Ong, Marcus Dörr, Heyo K. Kroemer, Uwe Völker, Henry Völzke, Pilar Galán, Serge Herçberg, Mark Lathrop, Diana Zélénika, Panos Deloukas, Massimo Mangino, Tim D. Spector, Guangju Zhai, James F. Meschia, Michael A. Nalls, Pankaj Sharma, Janoš Terzić, M. V. Kranthi Kumar, Matthew Denniff, E Zukowska-Szczechowska, Lynne E. Wagenknecht, F.G.R. Fowkes, Fadi J. Charchar, Peter Schwarz, Caroline Hayward, Xiuqing Guo, Charles N. Rotimi, Michiel L. Bots, Eva Brand, Nilesh J. Samani, Ozren Polašek, Philippa J. Talmud, Fredrik Nyberg, Diana Kuh, Maris Laan, Kristian Hveem, Lyle J. Palmer, Yvonne T. van der Schouw, Juan P. Casas, Karen L. Mohlke, Paolo Vineis, Olli T. Raitakari, Santhi K. Ganesh, Tien Yin Wong, E Shyong Tai, Richard S. Cooper, Markku Laakso, D. C. Rao, Tamara B. Harris, Richard Morris, Anna F. Dominiczak, Mika Kivimäki, Michael Marmot, Tetsuro Miki, Danish Saleheen, Giriraj R. Chandak, Josef Coresh, Gerjan Navis, Veikko Salomaa, Bok‐Ghee Han, Xiaofeng Zhu, Jaspal S. Kooner, Olle Melander, Paul M. Ridker, Stefania Bandinelli, Ulf Gyllensten, Alan F. Wright, James F. Wilson, Luigi Ferrucci, Martin Farrall, Jaakko Tuomilehto, Peter P. Pramstaller, Roberto Elosúa, Nicole Soranzo, Eric J.G. Sijbrands, David Altshuler, Ruth J. F. Loos, Alan R. Shuldiner, Christian Gieger, Pierre Meneton, André G. Uitterlinden, Nicholas J. Wareham, Vilmundur Guðnason, Jerome I. Rotter, Rainer Rettig, Manuela Uda, David P. Strachan, Jacqueline C.M. Witteman, Anna‐Liisa Hartikainen, J. Beckmann, Eric Boerwinkle, Ramachandran S. Vasan, Michael Boehnke, Martin G. Larson, Marjo‐Riitta Järvelin, Bruce M. Psaty, Gonçalo R. Abecasis, Aravinda Chakravarti, Paul Elliott, Cornelia M. van Duijn, Christopher Newton‐Cheh, Daniel Levy, Mark J. Caulfield, Toby Johnson, Aad van der Lugt, Aaron Isaacs, Abbas Dehghan, Afshin Parsa, Alan R. Shuldiner, Albert Hofman, Albert V. Smith, Aldi T. Kraja, André G. Uitterlinden, André G. Uitterlinden, Andreas Ziegler, Andrew D. Johnson, Angelo Scuteri, Anne B. Newman, Arne Schillert, Benjamin F. Voight, Ben A. Oostra, Bolli Þórsson, Braxton D. Mitchell, Bruce M. Psaty, Caroline Hayward, Caroline S. Fox, Charles C. White, Christa Meisinger, Christie M. Ballantyne, Cornelia M. van Duijn, David Altshuler, David M. Herrington, Daniel H. O’Leary, David S. Siscovick, David Couper, Edward G. Lakatta, Eran Halperin, Eric Boerwinkle, Eva‐Maria Stoegerer, Fernando Rivadeneira, Florian Ernst, Gabriël P. Krestin, Georg Homuth, Gerardo Heiss, Gianluca Usala, Gonçalo R. Abecasis, Guðný Eiríksdóttir, Haiqing Shen, H.-Erich Wichmann, Helena Schmidt, Henry Völzke, Ingrid B. Borecki, Hugh S. Markus, Jacqueline C.M. Witteman, James F. Wilson, Jan Lüdemann, Jeffrey R. O’Connell, Jennifer E. Huffman, Jens Baumert, Jerome I. Rotter, Joanne M. Murabito, Joachim Thiery, Jochen Seißler, Jorma Viikari, Joseph M. Massaro, Joseph F. Polak, Julie M. Cunningham, Joshua C. Bis, Kari E. North, Katja Petrovic, Kenneth Rice, Kent D. Taylor, L. Adrienne Cupples, Lawrence F. Bielak, Leena Peltonen, Lenore J. Launer, Mariza de Andrade, Manuela Uda, Marco Orrù, Marcus Dörr, Mary F. Feitosa, Maryam Kavousi, Matthias Sitzer, Matthijs Oudkerk, Michael A. Province, Michael A. Nalls, Mika Kähönen, Muredach P. Reilly, Nicole L. Glazer, Nora Franceschini, Norman Klopp, Olli T. Raitakari, Patricia A. Peyser, Philip A. Wolf, Qunyuan Zhang, Philipp S. Wild, Renate B. Schnabel, Roberto Elosúa, Ralph B. D’Agostino, Ravi Kumar Chilukoti, Reinhold Schmidt, Renate B. Schnabel, Sekar Kathiresan, Serena Sanna, Sharon L. R. Kardia, Shih‐Jen Hwang, Serkalem Demissie, Sigurður Sigurðsson, Stephen M. Schwartz, Stefan Blankenberg, Steve Bevan, Suzette E. Elias‐Smale, Susan R. Heckbert, Tamara B. Harris, Tanja Zeller, Terho Lehtimäki, Thomas Illig, Thomas Münzel, Thor Aspelund, Timothy D. Howard, Udo Hoffmann, Ulf Schminke, Veikko Salomaa, Vijay Nambi, Vilmundur Guðnason, Ching‐Ti Liu, Yan V. Sun, Wendy S. Post, Wolfgang Köenig, Wolfgang Rathmann, Xia Li, Yu‐Ching Cheng - Journal of the American Heart Association 2017 cited by 134

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.