Genetic variation in SCN10A influences cardiac conduction

被引：217

作者：

Chambers, John C. ^{[1
,2
]}

Zhao, Jing ^{[3
]}

Terracciano, Cesare M. N. ^{[4
]}

Bezzina, Connie R. ^{[5
,6
]}

Zhang, Weihua ^{[1
,2
]}

Kaba, Riyaz ^{[4
]}

Navaratnarajah, Manoraj ^{[4
]}

Lotlikar, Amol ^{[3
]}

Sehmi, Joban S. ^{[2
,4
]}

Kooner, Manraj K. ^{[2
,4
]}

Deng, Guohong ^{[2
,7
]}

Siedlecka, Urszula ^{[4
]}

Parasramka, Saurabh ^{[2
]}

El-Hamamsy, Ismail ^{[4
]}

Wass, Mark N. ^{[8
]}

Dekker, Lukas R. C. ^{[6
]}

de Jong, Jonas S. S. G. ^{[6
]}

Sternberg, Michael J. E. ^{[8
]}

McKenna, William ^{[9
]}

Severs, Nicholas J. ^{[4
]}

de Silva, Ranil ^{[2
,4
]}

Wilde, Arthur A. M. ^{[5
,6
]}

Anand, Praveen ^{[10
]}

Yacoub, Magdi ^{[4
]}

Scott, James ^{[4
]}

Elliott, Paul ^{[1
]}

Wood, John N. ^{[3
]}

Kooner, Jaspal S. ^{[2
,4
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England

[2] Ealing Hosp Natl Hlth Serv NHS Trust, Middlesex, England

[3] UCL, Wolfson Inst Biomed Res, London, England

[4] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[5] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[6] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands

[7] Univ London Imperial Coll Sci Technol & Med, Dept Gastroenterol & Hepatol, London, England

[8] Univ London Imperial Coll Sci Technol & Med, Struct Bioinformat Grp, London, England

[9] UCL, Inst Cardiovasc Sci, London, England

[10] Univ London Imperial Coll Sci Technol & Med, Dept Clin Neurosci, London, England

来源：

NATURE GENETICS | 2010年 / 42卷 / 02期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

SODIUM-CHANNEL NA(V)1.8; QT INTERVAL DURATION; COMMON VARIANTS; SUDDEN-DEATH; DRG NEURONS; MORTALITY; HEART; DISEASE; BURDEN; PAIN;

D O I：

10.1038/ng.516

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 x 10(-15)) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10(-5) to 10(-20)). SCN10A encodes Na(V)1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a(-/-) mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.

引用

页码：149 / U80

页数：5

共 33 条

[1] The cell and molecular basis of mechanical, cold, and inflammatory pain [J].

Abrahamsen, Bjarke ;

Zhao, Jing ;

Asante, Curtis O. ;

Cendan, Cruz Miguel ;

Marsh, Steve ;

Martinez-Barbera, Juan Pedro ;

Nassar, Mohammed A. ;

Dickenson, Anthony H. ;

Wood, John N. .

SCIENCE, 2008, 321 (5889) :702-705

[2] 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

[3] A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons [J].

Akopian, AN ;

Sivilotti, L ;

Wood, JN .

NATURE, 1996, 379 (6562) :257-262

[4] Common genetic variation near MC4R is associated with waist circumference and insulin resistance [J].

Chambers, John C. ;

Elliott, Paul ;

Zabaneh, Delilah ;

Zhang, Weihua ;

Li, Yun ;

Froguel, Philippe ;

Balding, David ;

Scott, James ;

Kooner, Jaspal S. .

NATURE GENETICS, 2008, 40 (06) :716-718

[5] Familial sudden death is an important risk factor for primary ventricular fibrillation - A case-control study in acute myocardial infarction patients [J].

Dekker, Lukas R. C. ;

Bezzina, Connie R. ;

Henriques, Jose P. S. ;

Tanck, Michael W. ;

Koch, Karel T. ;

Alings, Marco W. ;

Arnold, Alfred E. R. ;

de Boer, Menko-Jan ;

Gorgels, Anton P. M. ;

Michels, H. Rolf ;

Verkerk, Agnes ;

Verheugt, Freek W. A. ;

Zijlstra, Felix ;

Wilde, Arthur A. M. .

CIRCULATION, 2006, 114 (11) :1140-1145

[6] The TTX-resistant sodium channel Nav1.8(SNS/PN3):: expression and correlation with membrane properties in rat nociceptive primary afferent neurons [J].

Djouhri, L ;

Fang, X ;

Okuse, K ;

Wood, JN ;

Berry, CM ;

Lawson, SN .

JOURNAL OF PHYSIOLOGY-LONDON, 2003, 550 (03) :739-752

[7] The metabolic syndrome [J].

Eckel, RH ;

Grundy, SM ;

Zimmet, PZ .

LANCET, 2005, 365 (9468) :1415-1428

[8] cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-dependent sodium channel SNS [J].

Fitzgerald, EM ;

Okuse, K ;

Wood, JN ;

Dolphin, AC ;

Moss, SJ .

JOURNAL OF PHYSIOLOGY-LONDON, 1999, 516 (02) :433-446

[9] Inactivation properties of sodium channel Nav1.8 maintain action potential amplitude in small DRG neurons in the context of depolarization [J].

Harty, T. Patrick ;

Waxman, Stephen G. .

MOLECULAR PAIN, 2007, 3

[10] Medical progress: Sudden death due to cardiac arrhythmias [J].

Huikuri, HV ;

Castellanos, A ;

Myerburg, RJ .

NEW ENGLAND JOURNAL OF MEDICINE, 2001, 345 (20) :1473-1482

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