Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease
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 M. K.;Dehghan, Abbas;Silbernagel, Günther;Schrijvers, Elisabeth M. C.;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.;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.;Hwang, Shih-Jen;Pihur, Vasyl;Vollenweider, Peter;O'Reilly, Paul F.;Amin, Najaf;Bragg-Gresham, Jennifer L.;Teumer, Alexander;Glazer, Nicole L.;Launer, Lenore;Zhao, Jing Hua;Aulchenko, Yurii;Heath, Simon;Sõber, Siim;Parsa, Afshin;Luan, Jian'an;Arora, Pankaj;Zhang, Feng;Lucas, Gavin;Hicks, Andrew A.;Jackson, Anne U.;Tanaka, Toshiko;Wild, Sarah H.;Rudan, Igor;Igl, Wilmar;Milaneschi, Yuri;Parker, Alex N.;Fava, Cristiano;Fox, Ervin R.;Kumari, Meena;Go, Min Jin;Linda Kao, Wen Hong;Sjögren, Marketa;Vinay, D. G.;Alexander, Myriam;Tabara, Yasuharu;Shaw-Hawkins, Sue;Whincup, Peter H.;Shi, Gang;Kuusisto, Johanna;Tayo, Bamidele;Seielstad, Mark;Sim, Xueling;Nguyen, Khanh-Dung Hoang;Lehtimäki, Terho;Matullo, Giuseppe;Wu, Ying;Gaunt, Tom R.;Onland-Moret, N. Charlotte;Cooper, Matthew N.;Platou, Carl G. P.;Org, Elin;Hardy, Rebecca;Dahgam, Santosh;Palmen, Jutta;Vitart, Veronique;Braund, Peter S.;Kuznetsova, Tatiana;Uiterwaal, Cuno S. P. M.;Adeyemo, Adebowale;Palmas, Walter;Campbell, Harry;Ludwig, Barbara;Tomaszewski, Maciej;Tzoulaki, Ioanna;Palmer, Nicholette D.;Aspelund, Thor;Garcia, Melissa;Chang, Yen-Pei C.;O'Connell, Jeffrey R.;Steinle, Nanette I.;Grobbee, Diederick E.;Arking, Dan E.;Kardia, Sharon L.;Morrison, Alanna C.;Hernandez, Dena;Najjar, Samer;McArdle, Wendy L.;Hadley, David;Brown, Morris J.;Connell, John M.;Hingorani, Aroon D.;Day, Ian N. M.;Lawlor, Debbie A.;Beilby, John P.;Lawrence, Robert W.;Ongen, Halit;Dreisbach, Albert W.;Li, Yali;Young, J. Hunter;Kähönen, Mika;Viikari, Jorma;Adair, Linda S.;Lee, Nanette R.;Olden, Matthias;Pattaro, Cristian;Hoffman Bolton, Judith A.;Köttgen, Anna;Bergmann, Sven;Mooser, Vincent;Chaturvedi, Nish;Frayling, Timothy M.;Islam, Muhammad;Jafar, Tazeen H.;Erdmann, Jeanette;Kulkarni, Smita R.;Bornstein, Stefan R.;Grässler, Jürgen;Groop, Leif;Voight, Benjamin F.;Kettunen, Johannes;Howard, Philip;Taylor, Andrew;Guarrera, Simonetta;Ricceri, Fulvio;Emilsson, Valur;Plump, Andrew;Barroso, Inês;Khaw, Kay-Tee;Weder, Alan B.;Hunt, Steven C.;Sun, Yan V.;Bergman, Richard N.;Collins, Francis S.;Bonnycastle, Lori L.;Scott, Laura J.;Stringham, Heather M.;Peltonen, Leena;Perola, Markus;Vartiainen, Erkki;Brand, Stefan-Martin;Staessen, Jan A.;Wang, Thomas J.;Burton, Paul R.;Artigas, Maria Soler;Dong, Yanbin;Snieder, Harold;Wang, Xiaoling;Zhu, Haidong;Lohman, Kurt K.;Rudock, Megan E.;Heckbert, Susan R.;Wiggins, Kerri L.;Doumatey, Ayo;Shriner, Daniel;Veldre, Gudrun;Viigimaa, Margus;Kinra, Sanjay;Prabhakaran, Dorairaj;Tripathy, Vikal;Langefeld, Carl D.;Rosengren, Annika;Thelle, Dag S.;Corsi, Anna Maria;Singleton, Andrew;Forrester, Terrence;Hilton, Gina;McKenzie, Colin A.;Salako, Tunde;Iwai, Naoharu;Kita, Yoshikuni;Ogihara, Toshio;Ohkubo, Takayoshi;Okamura, Tomonori;Ueshima, Hirotsugu;Umemura, Satoshi;Eyheramendy, Susana;Meitinger, Thomas;Wichmann, H. -Erich;Cho, Yoon Shin;Kim, Hyung-Lae;Lee, Jong-Young;Scott, James;Sehmi, Joban S.;Zhang, Weihua;Hedblad, Bo;Nilsson, Peter;Smith, George Davey;Wong, Andrew;Narisu, Narisu;Stančáková, Alena;Raffel, Leslie J.;Yao, Jie;Schwartz, Stephen M.;Arfan Ikram, M.;Longstreth, W. T.;Mosley, Thomas H.;Seshadri, Sudha;Shrine, Nick R. G.;Wain, Louise V.;Morken, Mario A.;Swift, Amy J.;Laitinen, Jaana;Prokopenko, Inga;Zitting, Paavo;Cooper, Jackie A.;Humphries, Steve E.;Rasheed, Asif;Bakker, Stephan J. L.;Janipalli, Charles S.;Mani, K. Radha;Yajnik, Chittaranjan S.;Mattace-Raso, Francesco U. S.;Oostra, Ben A.;Demirkan, Ayse;Isaacs, Aaron;Rivadeneira, Fernando;Lakatta, Edward G.;Orru, Marco;Scuteri, Angelo;Ala-Korpela, Mika;Kangas, Antti J.;Lyytikäinen, Leo-Pekka;Soininen, Pasi;Tukiainen, Taru;Würtz, Peter;Ong, Rick Twee-Hee;Dörr, Marcus;Kroemer, Heyo K.;Völker, Uwe;Völzke, Henry;Galan, Pilar;Hercberg, Serge;Lathrop, Mark;Zelenika, Diana;Deloukas, Panos;Mangino, Massimo;Zhai, Guangju;Meschia, James F.;Nalls, Michael A.;Sharma, Pankaj;Terzic, Janos;Kumar, M. V. Kranthi;Denniff, Matthew;Zukowska-Szczechowska, Ewa;Wagenknecht, Lynne E.;Fowkes, F. Gerald R.;Charchar, Fadi J.;Schwarz, Peter E. H.;Hayward, Caroline;Guo, Xiuqing;Rotimi, Charles;Bots, Michiel L.;Brand, Eva;Samani, Nilesh J.;Polasek, Ozren;Talmud, Philippa J.;Nyberg, Fredrik;Kuh, Diana;Laan, Maris;Hveem, Kristian;Palmer, Lyle J.;van der Schouw, Yvonne T.;Casas, Juan P.;Mohlke, Karen L.;Vineis, Paolo;Raitakari, Olli;Ganesh, Santhi K.;Wong, Tien Y.;Shyong Tai, E.;Cooper, Richard S.;Laakso, Markku;Rao, Dabeeru C.;Morris, Richard W.;Dominiczak, Anna F.;Kivimaki, Mika;Marmot, Michael G.;Miki, Tetsuro;Chandak, Giriraj R.;Coresh, Josef;Navis, Gerjan;Salomaa, Veikko;Han, Bok-Ghee;Zhu, Xiaofeng;Melander, Olle;Ridker, Paul M.;Bandinelli, Stefania;Gyllensten, Ulf B.;Wright, Alan F.;Wilson, James F.;Ferrucci, Luigi;Farrall, Martin;Tuomilehto, Jaakko;Pramstaller, Peter P.;Elosua, Roberto;Sijbrands, Eric J. G.;Altshuler, David;Loos, Ruth J. F.;Gieger, Christian;Meneton, Pierre;Wareham, Nicholas J.;Gudnason, Vilmundur;Rotter, Jerome I.;Rettig, Rainer;Uda, Manuela;Strachan, David P.;Witteman, Jacqueline C. M.;Hartikainen, Anna-Liisa;Beckmann, Jacques S.;Boerwinkle, Eric;Vasan, Ramachandran S.;Boehnke, Michael;Larson, Martin G.;Järvelin, Marjo-Riitta;Abecasis, Gonçalo R.;Chakravarti, Aravinda;Elliott, Paul;van Duijn, Cornelia M.;Newton-Cheh, Christopher;Levy, Daniel;Caulfield, Mark J.;Johnson, Toby;van der Lugt, Aad;Shuldiner, Alan R.;Hofman, Albert;Kraja, Aldi T.;Uitterlinden, Andre;Ziegler, Andreas;Newman, Anne B.;Schillert, Arne;Oostra, Ben;Thorsson, Bolli;Mitchell, Braxton D.;Fox, Caroline S.;White, Charles C.;Ballantyne, Christie;Duijn, Cornelia van;Herrington, David M.;O'Leary, Daniel H.;Siscovick, David S.;Couper, David J.;Halperin, Eran;Stoegerer, Eva-Maria;Ernst, Florian;Krestin, Gabriel P.;Homuth, Georg;Heiss, Gerardo;Usala, Gianluca;Eiriksdottir, Gudny;Shen, Haiqing;Erich Wichmann, H.;Schmidt, Helena;Borecki, Ingrid B.;Markus, Hugh S.;Witteman, Jacqueline;Lüdemann, Jan;Huffman, Jennifer E.;Murabito, Joanne M.;Thiery, Joachim;Seissler, Jochen;Massaro, Joseph M.;Polak, Joseph F.;Cunningham, Julie;North, Kari;Petrovic, Katja E.;Rice, Kenneth;Adrienne Cupples, L.;Bielak, Lawrence F.;Launer, Lenore J.;Andrade, Mariza de;Feitosa, Mary F.;Kavousi, Maryam;Sitzer, Matthias;Oudkerk, Matthijs;Province, Michael A.;Nalls, Michael;Franceschini, Nora;Peyser, Patricia A.;Wolf, Philip A.;Zhang, Qunyuan;Wild, Philipp S.;Schnabel, Renate B.;D'Agostino, Ralph B.;Chilukoti, Ravi Kumar;Schmidt, Reinhold;Sanna, Serena;Demissie, Serkalem;Sigurdsson, Sigurdur;Blankenberg, Stefan;Bevan, Steve;Elias-Smale, Suzette E.;Zeller, Tanja;Illig, Thomas;Münzel, Thomas;Howard, Timothy D.;Hoffmann, Udo;Schminke, Ulf;Nambi, Vijay;Post, Wendy S.;Rathmann, Wolfgang;Li, Xia;Cheng, Yu-Ching
2017-01-01
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.