1. Genetic variation in SCN10A influences cardiac conduction
- Author
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John N. Wood, Lukas R.C. Dekker, Urszula Siedlecka, Jaspal S. Kooner, Nicholas J. Severs, Riyaz A. Kaba, Amol Lotlikar, Joban Sehmi, Magdi H. Yacoub, Jonas S.S.G. de Jong, Manraj K. Kooner, Mark N. Wass, Michael J.E. Sternberg, Paul Elliott, Guohong Deng, Cesare M. Terracciano, Saurabh Parasramka, Arthur A.M. Wilde, William J. McKenna, James Scott, Manoraj Navaratnarajah, Weihua Zhang, Connie R. Bezzina, John C. Chambers, Praveen Anand, Ranil de Silva, Ismail El-Hamamsy, Jing Zhao, Graduate School, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Other departments
- Subjects
Adult ,Male ,medicine.medical_specialty ,Heart block ,India ,Biology ,Polymorphism, Single Nucleotide ,Sudden death ,Sodium Channels ,NAV1.8 Voltage-Gated Sodium Channel ,Electrocardiography ,Mice ,QRS complex ,Asian People ,Heart Conduction System ,Heart Rate ,Internal medicine ,Cardiac conduction ,Genetics ,medicine ,Animals ,Humans ,Telemetry ,Genetic Predisposition to Disease ,PR interval ,Aged ,Oligonucleotide Array Sequence Analysis ,medicine.diagnostic_test ,Genetic Variation ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Europe ,Heart Block ,Genetic Loci ,Ventricular Fibrillation ,Ventricular fibrillation ,cardiovascular system ,Cardiology ,Female ,Chromosomes, Human, Pair 3 ,Electrical conduction system of the heart ,Genome-Wide Association Study - 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 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.
- Published
- 2010
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