Yunju Yang1, Traci M Bartz2,3, Michael R Brown4, Xiuqing Guo5, Nuno R Zilhão6, Stella Trompet7,8, Stefan Weiss9,10, Jie Yao5, Jennifer A Brody2, Christopher R Defilippi11, Ron C Hoogeveen12, Henry J Lin5, Vilmundur Gudnason6,13, Christie M Ballantyne12,14, Marcus Dörr10,15, J Wouter Jukema7,16,17, Astrid Petersmann18, Bruce M Psaty2,19,20, Jerome I Rotter5, Eric Boerwinkle4, Myriam Fornage1,4, Goo Jun4, Bing Yu4. 1. The Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Houston, TX (Y.Y., M.F.). 2. Cardiovascular Health Research Unit, Department of Medicine (T.M.B., J.A.B., B.M.P.), University of Washington, Seattle, WA. 3. Department of Biostatistics (T.M.B.), University of Washington, Seattle, WA. 4. Department of Epidemiology, Human Genetics & Environmental Sciences and Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX (M.R.B., E.B., M.F., G.J., B.Y.). 5. Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.Y., H.J.L., J.I.R.). 6. Icelandic Heart Association, Kopavogur, Iceland (N.R.Z., V.G.). 7. Department of Cardiology (S.T., J.W.J.), Leiden University Medical Center, Leiden, the Netherlands. 8. Section of Gerontology and Geriatrics, Department of Internal Medicine (S.T.), Leiden University Medical Center, Leiden, the Netherlands. 9. Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and University of Greifswald, Greifswald, Germany (S.W.). 10. German Centre for Cardiovascular Research, Partner Site Greifswald, Greifswald, Germany (S.W., M.D.). 11. Inova Heart and Vascular Institute, Falls Church, VA (C.R.D.). 12. Division of Atherosclerosis and Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX (R.C.H., C.M.B.). 13. Faculty of Medicine, University of Iceland, Reykjavik, Iceland (V.G.). 14. Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, TX (C.M.B.). 15. Department of Internal Medicine B-Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine (M.D.), University Medicine Greifswald, Greifswald, Germany. 16. Einthoven Laboratory for Experimental Vascular Medicine (J.W.J.), Leiden University Medical Center, Leiden, the Netherlands. 17. Netherlands Heart Institute, Utrecht, the Netherlands (J.W.J.). 18. Institute of Clinical Chemistry and Laboratory Medicine (A.P.), University Medicine Greifswald, Greifswald, Germany. 19. Department of Epidemiology (B.M.P.), University of Washington, Seattle, WA. 20. Department of Health Services (B.M.P.), University of Washington, Seattle, WA.
Abstract
BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80×10-9). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI). CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.
BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80×10-9). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI). CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.
Entities:
Keywords:
Mendelian randomization analysis; cardiovascular diseases; genome-wide association study; heart failure; troponin I; troponin T
Authors: J Shepherd; G J Blauw; M B Murphy; S M Cobbe; E L Bollen; B M Buckley; I Ford; J W Jukema; M Hyland; A Gaw; A M Lagaay; I J Perry; P W Macfarlane; A E Meinders; B J Sweeney; C J Packard; R G Westendorp; C Twomey; D J Stott Journal: Am J Cardiol Date: 1999-11-15 Impact factor: 2.778
Authors: Euy-Myoung Jeong; Man Liu; Megan Sturdy; Ge Gao; Susan T Varghese; Ali A Sovari; Samuel C Dudley Journal: J Mol Cell Cardiol Date: 2011-09-25 Impact factor: 5.000
Authors: Matthias Wuttke; Yong Li; Man Li; Karsten B Sieber; Mary F Feitosa; Mathias Gorski; Adrienne Tin; Lihua Wang; Audrey Y Chu; Anselm Hoppmann; Holger Kirsten; Ayush Giri; Jin-Fang Chai; Gardar Sveinbjornsson; Bamidele O Tayo; Teresa Nutile; Christian Fuchsberger; Jonathan Marten; Massimiliano Cocca; Sahar Ghasemi; Yizhe Xu; Katrin Horn; Damia Noce; Peter J van der Most; Sanaz Sedaghat; Zhi Yu; Masato Akiyama; Saima Afaq; Tarunveer S Ahluwalia; Peter Almgren; Najaf Amin; Johan Ärnlöv; Stephan J L Bakker; Nisha Bansal; Daniela Baptista; Sven Bergmann; Mary L Biggs; Ginevra Biino; Michael Boehnke; Eric Boerwinkle; Mathilde Boissel; Erwin P Bottinger; Thibaud S Boutin; Hermann Brenner; Marco Brumat; Ralph Burkhardt; Adam S Butterworth; Eric Campana; Archie Campbell; Harry Campbell; Mickaël Canouil; Robert J Carroll; Eulalia Catamo; John C Chambers; Miao-Ling Chee; Miao-Li Chee; Xu Chen; Ching-Yu Cheng; Yurong Cheng; Kaare Christensen; Renata Cifkova; Marina Ciullo; Maria Pina Concas; James P Cook; Josef Coresh; Tanguy Corre; Cinzia Felicita Sala; Daniele Cusi; John Danesh; E Warwick Daw; Martin H de Borst; Alessandro De Grandi; Renée de Mutsert; Aiko P J de Vries; Frauke Degenhardt; Graciela Delgado; Ayse Demirkan; Emanuele Di Angelantonio; Katalin Dittrich; Jasmin Divers; Rajkumar Dorajoo; Kai-Uwe Eckardt; Georg Ehret; Paul Elliott; Karlhans Endlich; Michele K Evans; Janine F Felix; Valencia Hui Xian Foo; Oscar H Franco; Andre Franke; Barry I Freedman; Sandra Freitag-Wolf; Yechiel Friedlander; Philippe Froguel; Ron T Gansevoort; He Gao; Paolo Gasparini; J Michael Gaziano; Vilmantas Giedraitis; Christian Gieger; Giorgia Girotto; Franco Giulianini; Martin Gögele; Scott D Gordon; Daniel F Gudbjartsson; Vilmundur Gudnason; Toomas Haller; Pavel Hamet; Tamara B Harris; Catharina A Hartman; Caroline Hayward; Jacklyn N Hellwege; Chew-Kiat Heng; Andrew A Hicks; Edith Hofer; Wei Huang; Nina Hutri-Kähönen; Shih-Jen Hwang; M Arfan Ikram; Olafur S Indridason; Erik Ingelsson; Marcus Ising; Vincent W V Jaddoe; Johanna Jakobsdottir; Jost B Jonas; Peter K Joshi; Navya Shilpa Josyula; Bettina Jung; Mika Kähönen; Yoichiro Kamatani; Candace M Kammerer; Masahiro Kanai; Mika Kastarinen; Shona M Kerr; Chiea-Chuen Khor; Wieland Kiess; Marcus E Kleber; Wolfgang Koenig; Jaspal S Kooner; Antje Körner; Peter Kovacs; Aldi T Kraja; Alena Krajcoviechova; Holly Kramer; Bernhard K Krämer; Florian Kronenberg; Michiaki Kubo; Brigitte Kühnel; Mikko Kuokkanen; Johanna Kuusisto; Martina La Bianca; Markku Laakso; Leslie A Lange; Carl D Langefeld; Jeannette Jen-Mai Lee; Benjamin Lehne; Terho Lehtimäki; Wolfgang Lieb; Su-Chi Lim; Lars Lind; Cecilia M Lindgren; Jun Liu; Jianjun Liu; Markus Loeffler; Ruth J F Loos; Susanne Lucae; Mary Ann Lukas; Leo-Pekka Lyytikäinen; Reedik Mägi; Patrik K E Magnusson; Anubha Mahajan; Nicholas G Martin; Jade Martins; Winfried März; Deborah Mascalzoni; Koichi Matsuda; Christa Meisinger; Thomas Meitinger; Olle Melander; Andres Metspalu; Evgenia K Mikaelsdottir; Yuri Milaneschi; Kozeta Miliku; Pashupati P Mishra; Karen L Mohlke; Nina Mononen; Grant W Montgomery; Dennis O Mook-Kanamori; Josyf C Mychaleckyj; Girish N Nadkarni; Mike A Nalls; Matthias Nauck; Kjell Nikus; Boting Ning; Ilja M Nolte; Raymond Noordam; Jeffrey O'Connell; Michelle L O'Donoghue; Isleifur Olafsson; Albertine J Oldehinkel; Marju Orho-Melander; Willem H Ouwehand; Sandosh Padmanabhan; Nicholette D Palmer; Runolfur Palsson; Brenda W J H Penninx; Thomas Perls; Markus Perola; Mario Pirastu; Nicola Pirastu; Giorgio Pistis; Anna I Podgornaia; Ozren Polasek; Belen Ponte; David J Porteous; Tanja Poulain; Peter P Pramstaller; Michael H Preuss; Bram P Prins; Michael A Province; Ton J Rabelink; Laura M Raffield; Olli T Raitakari; Dermot F Reilly; Rainer Rettig; Myriam Rheinberger; Kenneth M Rice; Paul M Ridker; Fernando Rivadeneira; Federica Rizzi; David J Roberts; Antonietta Robino; Peter Rossing; Igor Rudan; Rico Rueedi; Daniela Ruggiero; Kathleen A Ryan; Yasaman Saba; Charumathi Sabanayagam; Veikko Salomaa; Erika Salvi; Kai-Uwe Saum; Helena Schmidt; Reinhold Schmidt; Ben Schöttker; Christina-Alexandra Schulz; Nicole Schupf; Christian M Shaffer; Yuan Shi; Albert V Smith; Blair H Smith; Nicole Soranzo; Cassandra N Spracklen; Konstantin Strauch; Heather M Stringham; Michael Stumvoll; Per O Svensson; Silke Szymczak; E-Shyong Tai; Salman M Tajuddin; Nicholas Y Q Tan; Kent D Taylor; Andrej Teren; Yih-Chung Tham; Joachim Thiery; Chris H L Thio; Hauke Thomsen; Gudmar Thorleifsson; Daniela Toniolo; Anke Tönjes; Johanne Tremblay; Ioanna Tzoulaki; André G Uitterlinden; Simona Vaccargiu; Rob M van Dam; Pim van der Harst; Cornelia M van Duijn; Digna R Velez Edward; Niek Verweij; Suzanne Vogelezang; Uwe Völker; Peter Vollenweider; Gerard Waeber; Melanie Waldenberger; Lars Wallentin; Ya Xing Wang; Chaolong Wang; Dawn M Waterworth; Wen Bin Wei; Harvey White; John B Whitfield; Sarah H Wild; James F Wilson; Mary K Wojczynski; Charlene Wong; Tien-Yin Wong; Liang Xu; Qiong Yang; Masayuki Yasuda; Laura M Yerges-Armstrong; Weihua Zhang; Alan B Zonderman; Jerome I Rotter; Murielle Bochud; Bruce M Psaty; Veronique Vitart; James G Wilson; Abbas Dehghan; Afshin Parsa; Daniel I Chasman; Kevin Ho; Andrew P Morris; Olivier Devuyst; Shreeram Akilesh; Sarah A Pendergrass; Xueling Sim; Carsten A Böger; Yukinori Okada; Todd L Edwards; Harold Snieder; Kari Stefansson; Adriana M Hung; Iris M Heid; Markus Scholz; Alexander Teumer; Anna Köttgen; Cristian Pattaro Journal: Nat Genet Date: 2019-05-31 Impact factor: 38.330
Authors: Stefan Blankenberg; Veikko Salomaa; Nataliya Makarova; Francisco Ojeda; Philipp Wild; Karl J Lackner; Torben Jørgensen; Barbara Thorand; Annette Peters; Matthias Nauck; Astrid Petersmann; Erkki Vartiainen; Giovanni Veronesi; Paolo Brambilla; Simona Costanzo; Licia Iacoviello; Gerard Linden; John Yarnell; Christopher C Patterson; Brendan M Everett; Paul M Ridker; Jukka Kontto; Renate B Schnabel; Wolfgang Koenig; Frank Kee; Tanja Zeller; Kari Kuulasmaa Journal: Eur Heart J Date: 2016-05-12 Impact factor: 29.983
Authors: Patrick Turley; Raymond K Walters; Omeed Maghzian; Aysu Okbay; James J Lee; Mark Alan Fontana; Tuan Anh Nguyen-Viet; Robbee Wedow; Meghan Zacher; Nicholas A Furlotte; Patrik Magnusson; Sven Oskarsson; Magnus Johannesson; Peter M Visscher; David Laibson; David Cesarini; Benjamin M Neale; Daniel J Benjamin Journal: Nat Genet Date: 2018-01-01 Impact factor: 38.330
Authors: Majid Nikpay; Anuj Goel; Hong-Hee Won; Leanne M Hall; Christina Willenborg; Stavroula Kanoni; Danish Saleheen; Theodosios Kyriakou; Christopher P Nelson; Jemma C Hopewell; Thomas R Webb; Lingyao Zeng; Abbas Dehghan; Maris Alver; Sebastian M Armasu; Kirsi Auro; Andrew Bjonnes; Daniel I Chasman; Shufeng Chen; Ian Ford; Nora Franceschini; Christian Gieger; Christopher Grace; Stefan Gustafsson; Jie Huang; Shih-Jen Hwang; Yun Kyoung Kim; Marcus E Kleber; King Wai Lau; Xiangfeng Lu; Yingchang Lu; Leo-Pekka Lyytikäinen; Evelin Mihailov; Alanna C Morrison; Natalia Pervjakova; Liming Qu; Lynda M Rose; Elias Salfati; Richa Saxena; Markus Scholz; Albert V Smith; Emmi Tikkanen; Andre Uitterlinden; Xueli Yang; Weihua Zhang; Wei Zhao; Mariza de Andrade; Paul S de Vries; Natalie R van Zuydam; Sonia S Anand; Lars Bertram; Frank Beutner; George Dedoussis; Philippe Frossard; Dominique Gauguier; Alison H Goodall; Omri Gottesman; Marc Haber; Bok-Ghee Han; Jianfeng Huang; Shapour Jalilzadeh; Thorsten Kessler; Inke R König; Lars Lannfelt; Wolfgang Lieb; Lars Lind; Cecilia M Lindgren; Marja-Liisa Lokki; Patrik K Magnusson; Nadeem H Mallick; Narinder Mehra; Thomas Meitinger; Fazal-Ur-Rehman Memon; Andrew P Morris; Markku S Nieminen; Nancy L Pedersen; Annette Peters; Loukianos S Rallidis; Asif Rasheed; Maria Samuel; Svati H Shah; Juha Sinisalo; Kathleen E Stirrups; Stella Trompet; Laiyuan Wang; Khan S Zaman; Diego Ardissino; Eric Boerwinkle; Ingrid B Borecki; Erwin P Bottinger; Julie E Buring; John C Chambers; Rory Collins; L Adrienne Cupples; John Danesh; Ilja Demuth; Roberto Elosua; Stephen E Epstein; Tõnu Esko; Mary F Feitosa; Oscar H Franco; Maria Grazia Franzosi; Christopher B Granger; Dongfeng Gu; Vilmundur Gudnason; Alistair S Hall; Anders Hamsten; Tamara B Harris; Stanley L Hazen; Christian Hengstenberg; Albert Hofman; Erik Ingelsson; Carlos Iribarren; J Wouter Jukema; Pekka J Karhunen; Bong-Jo Kim; Jaspal S Kooner; Iftikhar J Kullo; Terho Lehtimäki; Ruth J F Loos; Olle Melander; Andres Metspalu; Winfried März; Colin N Palmer; Markus Perola; Thomas Quertermous; Daniel J Rader; Paul M Ridker; Samuli Ripatti; Robert Roberts; Veikko Salomaa; Dharambir K Sanghera; Stephen M Schwartz; Udo Seedorf; Alexandre F Stewart; David J Stott; Joachim Thiery; Pierre A Zalloua; Christopher J O'Donnell; Muredach P Reilly; Themistocles L Assimes; John R Thompson; Jeanette Erdmann; Robert Clarke; Hugh Watkins; Sekar Kathiresan; Ruth McPherson; Panos Deloukas; Heribert Schunkert; Nilesh J Samani; Martin Farrall Journal: Nat Genet Date: 2015-09-07 Impact factor: 38.330