Genetic variation in SCN10A influences cardiac conduction

John C. Chambers; Jing Zhao; Cesare M.N. Terracciano; Connie R. Bezzina; Weihua Zhang; Riyaz Kaba; Manoraj Navaratnarajah; Amol Lotlikar; Joban S. Sehmi; Manraj K. Kooner; Guohong Deng; Urszula Siedlecka; Saurabh Parasramka; Ismail El-Hamamsy; Mark N. Wass; Lukas R.C. Dekker; Jonas S.S.G. De Jong; Michael J.E. Sternberg; William McKenna; Nicholas J. Severs; Ranil De Silva; Arthur A.M. Wilde; Praveen Anand; Magdi Yacoub; James Scott; Paul Elliott; John N. Wood; Jaspal S. Kooner

doi:10.1038/ng.516

Genetic variation in SCN10A influences cardiac conduction

John C. Chambers
, Jing Zhao
, Cesare M.N. Terracciano
, Connie R. Bezzina
, Weihua Zhang
, Riyaz Kaba
, Manoraj Navaratnarajah
, Amol Lotlikar
, Joban S. Sehmi
, Manraj K. Kooner
, Guohong Deng
, Urszula Siedlecka
, Saurabh Parasramka
, Ismail El-Hamamsy
, Mark N. Wass
, Lukas R.C. Dekker
, Jonas S.S.G. De Jong
, Michael J.E. Sternberg
, William McKenna
, Nicholas J. Severs

Ranil De Silva, Arthur A.M. Wilde, Praveen Anand, Magdi Yacoub, James Scott, Paul Elliott, John N. Wood, Jaspal S. Kooner

Research output: Contribution to journal › Article › peer-review

241 Scopus citations

Abstract

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 × 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 (GA) 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.

Original language	English
Pages (from-to)	149-152
Number of pages	4
Journal	Nature Genetics
Volume	42
Issue number	2
DOIs	https://doi.org/10.1038/ng.516
State	Published - Feb 2010
Externally published	Yes

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Chambers, J. C., Zhao, J., Terracciano, C. M. N., Bezzina, C. R., Zhang, W., Kaba, R., Navaratnarajah, M., Lotlikar, A., Sehmi, J. S., Kooner, M. K., Deng, G., Siedlecka, U., Parasramka, S., El-Hamamsy, I., Wass, M. N., Dekker, L. R. C., De Jong, J. S. S. G., Sternberg, M. J. E., McKenna, W., ... Kooner, J. S. (2010). Genetic variation in SCN10A influences cardiac conduction. Nature Genetics, 42(2), 149-152. https://doi.org/10.1038/ng.516

@article{811dcf1bbf2e4a9b8cad41653933615d,

title = "Genetic variation in SCN10A influences cardiac conduction",

abstract = "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 × 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 (GA) 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.",

author = "Chambers, \{John C.\} and Jing Zhao and Terracciano, \{Cesare M.N.\} and Bezzina, \{Connie R.\} and Weihua Zhang and Riyaz Kaba and Manoraj Navaratnarajah and Amol Lotlikar and Sehmi, \{Joban S.\} and Kooner, \{Manraj K.\} and Guohong Deng and Urszula Siedlecka and Saurabh Parasramka and Ismail El-Hamamsy and Wass, \{Mark N.\} and Dekker, \{Lukas R.C.\} and \{De Jong\}, \{Jonas S.S.G.\} and Sternberg, \{Michael J.E.\} and William McKenna and Severs, \{Nicholas J.\} and \{De Silva\}, Ranil and Wilde, \{Arthur A.M.\} and Praveen Anand and Magdi Yacoub and James Scott and Paul Elliott and Wood, \{John N.\} and Kooner, \{Jaspal S.\}",

note = "Funding Information: We thank the participants involved in the research. The LOLIPOP study was supported by the British Heart Foundation (SP/04/002) and by the Wellcome Trust (084723/Z/08/Z). Studies in the AGNES population were supported by the Netherlands Heart Foundation (Grant 2007B202) and the Leducq Foundation (Grant 05-CVD). J.Z. was supported by a BBSRC LOLA award (BB/F000227/1). R.K. was supported by the British Heart Foundation (Grant F/99089). M.N.W. is supported by the Biotechnology and Biological Sciences Research Council grant BB/F020481/1. W.M. is funded by the National Institute for Health Research Biomedical Research Centres scheme. J.N.W. is a member of the Wellcome Trust-funded London Pain Consortium. We thank G. Turner and M. Minett for maintaining the Scn10a-null mutant mouse colony, M.W. Tanck and R. Pazoki for help in statistical analyses and S. Rothery for technical assistance.",

year = "2010",

month = feb,

doi = "10.1038/ng.516",

language = "English",

volume = "42",

pages = "149--152",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "2",

}

Chambers, JC, Zhao, J, Terracciano, CMN, Bezzina, CR, Zhang, W, Kaba, R, Navaratnarajah, M, Lotlikar, A, Sehmi, JS, Kooner, MK, Deng, G, Siedlecka, U, Parasramka, S, El-Hamamsy, I, Wass, MN, Dekker, LRC, De Jong, JSSG, Sternberg, MJE, McKenna, W, Severs, NJ, De Silva, R, Wilde, AAM, Anand, P, Yacoub, M, Scott, J, Elliott, P, Wood, JN & Kooner, JS 2010, 'Genetic variation in SCN10A influences cardiac conduction', Nature Genetics, vol. 42, no. 2, pp. 149-152. https://doi.org/10.1038/ng.516

TY - JOUR

T1 - Genetic variation in SCN10A influences cardiac conduction

AU - Chambers, John C.

AU - Zhao, Jing

AU - Terracciano, Cesare M.N.

AU - Bezzina, Connie R.

AU - Zhang, Weihua

AU - Kaba, Riyaz

AU - Navaratnarajah, Manoraj

AU - Lotlikar, Amol

AU - Sehmi, Joban S.

AU - Kooner, Manraj K.

AU - Deng, Guohong

AU - Siedlecka, Urszula

AU - Parasramka, Saurabh

AU - El-Hamamsy, Ismail

AU - Wass, Mark N.

AU - Dekker, Lukas R.C.

AU - De Jong, Jonas S.S.G.

AU - Sternberg, Michael J.E.

AU - McKenna, William

AU - Severs, Nicholas J.

AU - De Silva, Ranil

AU - Wilde, Arthur A.M.

AU - Anand, Praveen

AU - Yacoub, Magdi

AU - Scott, James

AU - Elliott, Paul

AU - Wood, John N.

AU - Kooner, Jaspal S.

N1 - Funding Information: We thank the participants involved in the research. The LOLIPOP study was supported by the British Heart Foundation (SP/04/002) and by the Wellcome Trust (084723/Z/08/Z). Studies in the AGNES population were supported by the Netherlands Heart Foundation (Grant 2007B202) and the Leducq Foundation (Grant 05-CVD). J.Z. was supported by a BBSRC LOLA award (BB/F000227/1). R.K. was supported by the British Heart Foundation (Grant F/99089). M.N.W. is supported by the Biotechnology and Biological Sciences Research Council grant BB/F020481/1. W.M. is funded by the National Institute for Health Research Biomedical Research Centres scheme. J.N.W. is a member of the Wellcome Trust-funded London Pain Consortium. We thank G. Turner and M. Minett for maintaining the Scn10a-null mutant mouse colony, M.W. Tanck and R. Pazoki for help in statistical analyses and S. Rothery for technical assistance.

PY - 2010/2

Y1 - 2010/2

N2 - 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 × 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 (GA) 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.

AB - 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 × 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 (GA) 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.

UR - https://www.scopus.com/pages/publications/75749102498

U2 - 10.1038/ng.516

DO - 10.1038/ng.516

M3 - Article

C2 - 20062061

AN - SCOPUS:75749102498

SN - 1061-4036

VL - 42

SP - 149

EP - 152

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Genetic variation in SCN10A influences cardiac conduction

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