Genome-Wide Association Studies of the PR Interval in African Americans

被引：75

作者：

Smith, J. Gustav ^{[1
,2
,3
]}

Magnani, Jared W. ^{[4
,5
]}

Palmer, Cameron ^{[2
,3
]}

Meng, Yan A. ^{[2
,3
]}

Soliman, Elsayed Z. ^{[6
]}

Musani, Solomon K. ^{[7
]}

Kerr, Kathleen F. ^{[8
]}

Schnabel, Renate B. ^{[9
]}

Lubitz, Steven A. ^{[10
,11
,12
]}

Sotoodehnia, Nona ^{[13
]}

Redline, Susan ^{[14
]}

Pfeufer, Arne ^{[15
,16
]}

Mueller, Martina ^{[17
,18
,19
]}

Evans, Daniel S. ^{[20
]}

Nalls, Michael A. ^{[21
]}

Liu, Yongmei ^{[22
]}

Newman, Anne B. ^{[23
]}

Zonderman, Alan B. ^{[24
]}

Evans, Michele K. ^{[24
]}

Deo, Rajat ^{[25
]}

Ellinor, Patrick T. ^{[11
,12
,26
]}

Paltoo, Dina N. ^{[27
]}

Newton-Cheh, Christopher ^{[2
,3
,11
,12
,26
]}

Benjamin, Emelia J. ^{[28
,29
,30
]}

Mehra, Reena ^{[31
]}

Alonso, Alvaro ^{[32
]}

Heckbert, Susan R. ^{[33
]}

Fox, Ervin R. ^{[7
]}

机构：

[1] Lund Univ, Fac Med, Dept Cardiol, Lund, Sweden

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

[3] MIT, Cambridge, MA 02139 USA

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

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

[6] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Ctr EPICARE, Winston Salem, NC 27109 USA

[7] Univ Mississippi, Med Ctr, Jackson Heart Study, Dept Med,Div Cardiovasc Dis, Jackson, MS 39216 USA

[8] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA

[9] Johannes Gutenberg Univ Mainz, Med Clin Cardiol 2, Mainz, Germany

[10] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[11] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[12] Harvard Univ, Sch Med, Boston, MA USA

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

[14] Case Western Reserve Univ, Cleveland, OH 44106 USA

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

[16] Helmholtz Cent Munchen, Inst Human Genet, Neuherberg, Germany

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

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

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

[20] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA

[21] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[22] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA

[23] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA

[24] NIA, NIH, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA

[25] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA

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

[27] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA

[28] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA

[29] Boston Univ, Sch Med, Div Prevent Med, Boston, MA 02215 USA

[30] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA

[31] Case Sch Med, Dept Med, Cleveland, OH USA

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

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

来源：

PLOS GENETICS | 2011年 / 7卷 / 02期

基金：

美国国家卫生研究院;

关键词：

HEART-RATE; ATHEROSCLEROSIS RISK; GENETIC-ANALYSIS; COMMON VARIANTS; DESIGN; POPULATIONS; OBJECTIVES; CONDUCTION; DISEASE; TWINS;

D O I：

10.1371/journal.pgen.1001304

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p < 2.5 > 10(-8)) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta = 5.1 msec per minor allele, 95% CI = 4.1-6.1, p = 3 x 10(-23)). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8-3.0, p = 3 x 10(-16)) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity < 0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

引用

页数：9

共 34 条

[1] A haplotype map of the human genome [J].

Altshuler, D ;

Brooks, LD ;

Chakravarti, A ;

Collins, FS ;

Daly, MJ ;

Donnelly, P ;

Gibbs, RA ;

Belmont, JW ;

Boudreau, A ;

Leal, SM ;

Hardenbol, P ;

Pasternak, S ;

Wheeler, DA ;

Willis, TD ;

Yu, FL ;

Yang, HM ;

Zeng, CQ ;

Gao, Y ;

Hu, HR ;

Hu, WT ;

Li, CH ;

Lin, W ;

Liu, SQ ;

Pan, H ;

Tang, XL ;

Wang, J ;

Wang, W ;

Yu, J ;

Zhang, B ;

Zhang, QR ;

Zhao, HB ;

Zhao, H ;

Zhou, J ;

Gabriel, SB ;

Barry, R ;

Blumenstiel, B ;

Camargo, A ;

Defelice, M ;

Faggart, M ;

Goyette, M ;

Gupta, S ;

Moore, J ;

Nguyen, H ;

Onofrio, RC ;

Parkin, M ;

Roy, J ;

Stahl, E ;

Winchester, E ;

Ziaugra, L ;

Shen, Y .

NATURE, 2005, 437 (7063) :1299-1320

[2] Multi-ethnic study of atherosclerosis: Objectives and design [J].

Bild, DE ;

Bluemke, DA ;

Burke, GL ;

Detrano, R ;

Roux, AVD ;

Folsom, AR ;

Greenland, P ;

Jacobs, DR ;

Kronmal, R ;

Liu, K ;

Nelson, JC ;

O'Leary, D ;

Saad, MF ;

Shea, S ;

Szklo, M ;

Tracy, RP .

AMERICAN JOURNAL OF EPIDEMIOLOGY, 2002, 156 (09) :871-881

[3] Genetic variation in SCN10A influences cardiac conduction [J].

Chambers, John C. ;

Zhao, Jing ;

Terracciano, Cesare M. N. ;

Bezzina, Connie R. ;

Zhang, Weihua ;

Kaba, Riyaz ;

Navaratnarajah, Manoraj ;

Lotlikar, Amol ;

Sehmi, Joban S. ;

Kooner, Manraj K. ;

Deng, Guohong ;

Siedlecka, Urszula ;

Parasramka, Saurabh ;

El-Hamamsy, Ismail ;

Wass, Mark N. ;

Dekker, Lukas R. C. ;

de Jong, Jonas S. S. G. ;

Sternberg, Michael J. E. ;

McKenna, William ;

Severs, Nicholas J. ;

de Silva, Ranil ;

Wilde, Arthur A. M. ;

Anand, Praveen ;

Yacoub, Magdi ;

Scott, James ;

Elliott, Paul ;

Wood, John N. ;

Kooner, Jaspal S. .

NATURE GENETICS, 2010, 42 (02) :149-U80

[4] GWAF: an R package for genome-wide association analyses with family data [J].

Chen, Ming-Huei ;

Yang, Qiong .

BIOINFORMATICS, 2010, 26 (04) :580-581

[5] Long-term Outcomes in Individuals With Prolonged PR Interval or First-Degree Atrioventricular Block [J].

Cheng, Susan ;

Keyes, Michelle J. ;

Larson, Martin G. ;

McCabe, Elizabeth L. ;

Newton-Cheh, Christopher ;

Levy, Daniel ;

Benjamin, Emelia J. ;

Vasan, Ramachandran S. ;

Wang, Thomas J. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2009, 301 (24) :2571-2577

[6] Genomic control for association studies [J].

Devlin, B ;

Roeder, K .

BIOMETRICS, 1999, 55 (04) :997-1004

[7] A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia [J].

Dhandapany, Perundurai S. ;

Sadayappan, Sakthivel ;

Xue, Yali ;

Powell, Gareth T. ;

Rani, Deepa Selvi ;

Nallari, Prathiba ;

Rai, Taranjit Singh ;

Khullar, Madhu ;

Soares, Pedro ;

Bahl, Ajay ;

Tharkan, Jagan Mohan ;

Vaideeswar, Pradeep ;

Rathinavel, Andiappan ;

Narasimhan, Calambur ;

Ayapati, Dharma Rakshak ;

Ayub, Qasim ;

Mehdi, S. Qasim ;

Oppenheimer, Stephen ;

Richards, Martin B. ;

Price, Alkes L. ;

Patterson, Nick ;

Reich, David ;

Singh, Lalji ;

Tyler-Smith, Chris ;

Thangaraj, Kumarasamy .

NATURE GENETICS, 2009, 41 (02) :187-191

[8] GENETIC-FACTORS IN THE ELECTROCARDIOGRAM AND HEART-RATE OF TWINS REARED APART AND TOGETHER [J].

HANSON, B ;

TUNA, N ;

BOUCHARD, T ;

HESTON, L ;

ECKERT, E ;

LYKKEN, D ;

SEGAL, N ;

RICH, S .

AMERICAN JOURNAL OF CARDIOLOGY, 1989, 63 (09) :606-609

[9] VARIABILITY OF HEART-RATE, P-R, QRS AND Q-T DURATIONS IN TWINS [J].

HAVLIK, RJ ;

GARRISON, RJ ;

FABSITZ, R ;

FEINLEIB, M .

JOURNAL OF ELECTROCARDIOLOGY, 1980, 13 (01) :45-48

[10] Several common variants modulate heart rate, PR interval and QRS duration [J].

Holm, Hilma ;

Gudbjartsson, Daniel F. ;

Arnar, David O. ;

Thorleifsson, Gudmar ;

Thorgeirsson, Gudmundur ;

Stefansdottir, Hrafnhildur ;

Gudjonsson, Sigurjon A. ;

Jonasdottir, Aslaug ;

Mathiesen, Ellisiv B. ;

Njolstad, Inger ;

Nyrnes, Audhild ;

Wilsgaard, Tom ;

Hald, Erin M. ;

Hveem, Kristian ;

Stoltenberg, Camilla ;

Lochen, Maja-Lisa ;

Kong, Augustine ;

Thorsteinsdottir, Unnur ;

Stefansson, Kari .

NATURE GENETICS, 2010, 42 (02) :117-U40

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