Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease
Authors: Song Ci , Burgess Stephen , Eicher John D. ,   CHARGE Consortium Hemostatic Factor Working Group,   ICBP Consortium, 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. , 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 , Johnson Andrew D. , 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 , Dehghan Abbas , Zhang Feng , Lucas Gavin , Hicks Andrew A. , Jackson Anne U. , Peden John F. , Tanaka Toshiko , Wild Sarah H. , Rudan Igor , Igl Wilmar , Milaneschi Yuri , Parker Alex N. , Fava Cristiano , Chambers John C. , Fox Ervin R. , Kumari Meena , Go Min Jin , van der Harst Pim , Kao Wen Hong Linda , Sjögren Marketa , Vinay D. G. , Alexander Myriam , Tabara Yasuharu , Shaw‐Hawkins Sue , Whincup Peter H. , Liu Yongmei , 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. , Clarke Robert , Hopewell Jemma C. , Ongen Halit , Dreisbach Albert W. , Li Yali , Young J. Hunter , Bis Joshua C. , Kähönen Mika , Viikari Jorma , Adair Linda S. , Lee Nanette R. , Chen Ming‐Huei , 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. , Smith Nicholas L. , 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 , Kathiresan Sekar , 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. , Danesh John , Rasheed Asif , Goel Anuj , Hamsten Anders , Watkins Hugh , Bakker Stephan J. L. , van Gilst Wiek H. , Janipalli Charles S. , Mani K. Radha , Yajnik Chittaranjan S. , Hofman Albert , 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 , Spector Tim D. , Zhai Guangju , Meschia James F. , Nalls Michael A. , Sharma Pankaj , Terzic Janos , Kranthi Kumar M. V. , 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. , Tai E. Shyong , Cooper Richard S. , Laakso Markku , Rao Dabeeru C. , Harris Tamara B. , Morris Richard W. , Dominiczak Anna F. , Kivimaki Mika , Marmot Michael G. , Miki Tetsuro , Saleheen Danish , Chandak Giriraj R. , Coresh Josef , Navis Gerjan , Salomaa Veikko , Han Bok‐Ghee , Zhu Xiaofeng , Kooner Jaspal S. , 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 , Soranzo Nicole , Sijbrands Eric J. G. , Altshuler David , Loos Ruth J. F. , Shuldiner Alan R. , Gieger Christian , Meneton Pierre , Uitterlinden Andre G. , 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 , Psaty Bruce M. , 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 , Isaacs Aaron , Dehghan Abbas , Parsa Afshin , Shuldiner Alan R. , Hofman Albert , Smith Albert V. , Kraja Aldi T. , Uitterlinden Andre G. , Uitterlinden Andre , Ziegler Andreas , Johnson Andrew D. , Scuteri Angelo , Newman Anne B. , Schillert Arne , Voight Benjamin F. , Oostra Ben , Thorsson Bolli , Mitchell Braxton D. , Psaty Bruce M. , Hayward Caroline , Fox Caroline S. , White Charles C. , Meisinger Christa , Ballantyne Christie , van Duijn Cornelia , Altshuler David , Herrington David M. , O'Leary Daniel H. , Siscovick David S. , Couper David J. , Lakatta Edward G. , Halperin Eran , Boerwinkle Eric , Stoegerer Eva‐Maria , Rivadeneira Fernando , Ernst Florian , Krestin Gabriel P. , Homuth Georg , Heiss Gerardo , Usala Gianluca , Abecasis Gonçalo R. , Eiriksdottir Gudny , Shen Haiqing , Wichmann H. Erich , Schmidt Helena , Völzke Henry , Borecki Ingrid B. , Markus Hugh S. , Witteman Jacqueline , Wilson James F. , Lüdemann Jan , O'Connell Jeffrey R. , Huffman Jennifer E. , Baumert Jens , Rotter Jerome I. , Murabito Joanne M. , Thiery Joachim , Seissler Jochen , Viikari Jorma , Massaro Joseph M. , Polak Joseph F. , Cunningham Julie , Bis Joshua C. , North Kari , Petrovic Katja E. , Rice Kenneth , Taylor Kent , Cupples L. Adrienne , Bielak Lawrence F. , Peltonen Leena , Launer Lenore J. , de Andrade Mariza , Uda Manuela , Orru Marco , Dörr Marcus , Feitosa Mary F. , Kavousi Maryam , Sitzer Matthias , Oudkerk Matthijs , Province Michael A. , Nalls Michael , Kähönen Mika , Reilly Muredach P. , Glazer Nicole L. , Franceschini Nora , Klopp Norman , Raitakari Olli , Peyser Patricia A. , Wolf Philip A. , Zhang Qunyuan , Wild Philipp S. , Schnabel Renate B. , Elosua Roberto , D'Agostino Ralph B. , Chilukoti Ravi Kumar , Schmidt Reinhold , Schnabel Renate B. , Kathiresan Sekar , Sanna Serena , Kardia Sharon L. R. , Hwang Shih‐Jen , Demissie Serkalem , Sigurdsson Sigurdur , Schwartz Stephen M. , Blankenberg Stefan , Bevan Steve , Elias‐Smale Suzette E. , Heckbert Susan R. , Harris Tamara B. , Zeller Tanja , Lehtimäki Terho , Illig Thomas , Münzel Thomas , Aspelund Thor , Howard Timothy D. , Hoffmann Udo , Schminke Ulf , Salomaa Veikko , Nambi Vijay , Gudnason Vilmundur , Liu Yongmei , Sun Yan V. , Post Wendy S. , Koenig Wolfgang , Rathmann Wolfgang , Li Xia , Cheng Yu‐Ching 
Published: May 2017

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.