Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

被引：270

作者：

Sotoodehnia, Nona ^{[1
,2
]}

Isaacs, Aaron ^{[3
,4
]}

de Bakker, Paul I. W. ^{[5
,6
,7
,8
]}

Doerr, Marcus ^{[9
]}

Newton-Cheh, Christopher ^{[10
,11
,12
]}

Nolte, Ilja M. ^{[13
]}

van der Harst, Pim ^{[14
]}

Mueller, Martina ^{[15
,16
,17
]}

Eijgelsheim, Mark ^{[18
]}

Alonso, Alvaro ^{[19
]}

Hicks, Andrew A. ^{[20
,21
]}

Padmanabhan, Sandosh ^{[22
]}

Hayward, Caroline ^{[23
]}

Smith, Albert Vernon ^{[24
,25
]}

Polasek, Ozren ^{[26
]}

Giovannone, Steven ^{[27
]}

Fu, Jingyuan ^{[13
,28
]}

Magnani, Jared W. ^{[12
,29
]}

Marciante, Kristin D. ^{[2
]}

Pfeufer, Arne ^{[21
,30
,31
]}

Gharib, Sina A. ^{[32
]}

Teumer, Alexander ^{[33
]}

Li, Man ^{[34
,35
]}

Bis, Joshua C. ^{[2
]}

Rivadeneira, Fernando ^{[18
,36
]}

Aspelund, Thor ^{[24
,25
]}

Koettgen, Anna ^{[34
]}

Johnson, Toby ^{[37
,38
]}

Rice, Kenneth ^{[39
]}

Sie, Mark P. S. ^{[3
]}

Wang, Ying A. ^{[12
,40
]}

Klopp, Norman ^{[17
]}

Fuchsberger, Christian ^{[20
,21
]}

Wild, Sarah H. ^{[41
]}

Leach, Irene Mateo ^{[14
]}

Estrada, Karol ^{[36
]}

Voelker, Uwe ^{[33
]}

Wright, Alan F. ^{[23
]}

Asselbergs, Folkert W. ^{[13
,14
,42
]}

Qu, Jiaxiang ^{[27
]}

Chakravarti, Aravinda ^{[43
]}

Sinner, Moritz F. ^{[16
]}

Kors, Jan A. ^{[44
]}

Petersmann, Astrid ^{[45
]}

Harris, Tamara B. ^{[46
]}

Soliman, Elsayed Z. ^{[47
]}

Munroe, Patricia B. ^{[37
,38
]}

Psaty, Bruce M. ^{[2
,48
,49
,50
]}

Oostra, Ben A. ^{[4
,51
]}

Cupples, L. Adrienne ^{[12
,40
]}

机构：

[1] Univ Washington, Dept Med, Div Cardiol, Seattle, WA 98195 USA

[2] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[3] Erasmus Med Ctr MC, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands

[4] Ctr Med Syst Biol, Leiden, Netherlands

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA

[6] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[7] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands

[8] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[9] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, Greifswald, Germany

[10] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[11] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[12] NHLBI, Framingham Heart Study, Framingham, MA USA

[13] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, Groningen, Netherlands

[14] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[15] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[16] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany

[17] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[18] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[19] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[20] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy

[21] Univ Lubeck, Affiliated Inst, Lubeck, Germany

[22] Univ Glasgow, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland

[23] MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[24] Iceland Heart Assoc, Kopavogur, Iceland

[25] Univ Iceland, Reykjavik, Iceland

[26] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia

[27] NYU, Sch Med, Leon H Charney Div Cardiol, New York, NY USA

[28] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 AB Groningen, Netherlands

[29] Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA

[30] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[31] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany

[32] Univ Washington, Dept Med, Ctr Lung Biol, Seattle, WA USA

[33] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany

[34] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA

[35] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA

[36] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[37] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Clin Pharmacol & Barts & London Genome Ctr, London, England

[38] Barts & London Natl Inst Hlth Res, Cardiovasc Biomed Res Unit, London, England

[39] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[40] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[41] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[42] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[43] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[44] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands

[45] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[46] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA

[47] Wake Forest Univ, Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27109 USA

[48] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[49] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[50] Grp Hlth Cooperat Puget Sound, Gup Hlth Res Inst, Seattle, WA 98121 USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 12期

基金：

英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; QT INTERVAL DURATION; RICH REPEAT PROTEIN; HEART-RATE; TRANSCRIPTION FACTOR; GENE-EXPRESSION; PR INTERVAL; SYSTEM; DISEASE; ELECTROCARDIOGRAM;

D O I：

10.1038/ng.716

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

引用

页码：1068 / U62

页数：11

共 66 条

[1] Cardiac sodium channel Nav1.5 and interacting proteins: Physiology and pathophysiology [J].

Abriel, Hugues .

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2010, 48 (01) :2-11

[2] Wnt-1 regulation of connexin43 in cardiac myocytes [J].

Ai, ZW ;

Fischer, A ;

Spray, DC ;

Brown, AMC ;

Fishman, GI .

JOURNAL OF CLINICAL INVESTIGATION, 2000, 105 (02) :161-171

[3] The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways [J].

Akopian, AN ;

Souslova, V ;

England, S ;

Okuse, K ;

Ogata, N ;

Ure, J ;

Smith, A ;

Kerr, BJ ;

McMahon, SB ;

Boyce, S ;

Hill, R ;

Stanfa, LC ;

Dickenson, AH ;

Wood, JN .

NATURE NEUROSCIENCE, 1999, 2 (06) :541-548

[4] Molecular cloning and characterization of phocein, a protein found from the Golgi complex to dendritic spines [J].

Baillat, G ;

Moqrich, A ;

Castets, F ;

Baude, AS ;

Bailly, Y ;

Benmerah, A ;

Monneron, A .

MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (03) :663-673

[5] Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system [J].

Bakker, Martijn L. ;

Boukens, Bastiaan J. ;

Mommersteeg, Mathilda T. M. ;

Brons, Janynke F. ;

Wakker, Vincent ;

Moorman, Antoon F. M. ;

Christoffels, Vincent M. .

CIRCULATION RESEARCH, 2008, 102 (11) :1340-1349

[6] Involvement of p21Waf1/Cip1 in protein kinase C alpha-induced cell cycle progression [J].

Besson, A ;

Yong, VW .

MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (13) :4580-4590

[7] Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction [J].

Bezzina, CR ;

Shimizu, W ;

Yang, P ;

Koopmann, TT ;

Tanck, MWT ;

Miyamoto, Y ;

Kamakura, S ;

Roden, DM ;

Wilde, AAM .

CIRCULATION, 2006, 113 (03) :338-344

[8] Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43 [J].

Boogerd, Kees-Jan ;

Wong, L. Y. Elaine ;

Christoffels, Vincent M. ;

Klarenbeek, Meinke ;

Ruijter, Jan M. ;

Moorman, Antoon F. M. ;

Barnett, Phil .

CARDIOVASCULAR RESEARCH, 2008, 78 (03) :485-493

[9] PKC-α regulates cardiac contractility and propensity toward heart failure [J].

Braz, JC ;

Gregory, K ;

Pathak, A ;

Zhao, W ;

Sahin, B ;

Klevitsky, R ;

Kimball, TF ;

Lorenz, JN ;

Nairn, AC ;

Liggett, SB ;

Bodi, I ;

Wang, S ;

Schwartz, A ;

Lakatta, EG ;

DePaoli-Roach, AA ;

Robbins, J ;

Hewett, TE ;

Bibb, JA ;

Westfall, MV ;

Kranias, EG ;

Molkentin, JD .

NATURE MEDICINE, 2004, 10 (03) :248-254

[10] Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice [J].

Breckenridge, Ross A. ;

Zuberi, Zia ;

Gomes, John ;

Orford, Robert ;

Dupays, Laurent ;

Felkin, Leanne E. ;

Clark, James E. ;

Magee, Anthony I. ;

Ehler, Elisabeth ;

Birks, Emma J. ;

Barton, Paul J. R. ;

Tinker, Andrew ;

Mohun, Timothy J. .

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2009, 47 (01) :133-141

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