Genetic variation in SCN10A influences cardiac conduction.

TitleGenetic variation in SCN10A influences cardiac conduction.
Publication TypeJournal Article
Year of Publication2010
AuthorsChambers 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
JournalNat Genet
Volume42
Issue2
Pagination149-52
Date Published2010 Feb
ISSN1546-1718
KeywordsAdult, Aged, Animals, Asian Continental Ancestry Group, Chromosomes, Human, Pair 3, Electrocardiography, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Heart Block, Heart Conduction System, Heart Rate, Humans, India, Male, Mice, Middle Aged, NAV1.8 Voltage-Gated Sodium Channel, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Reproducibility of Results, Sodium Channels, Telemetry, Ventricular Fibrillation
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.

DOI10.1038/ng.516
Alternate JournalNat. Genet.
PubMed ID20062061
Grant List084723/Z/08/Z / / Wellcome Trust / United Kingdom
BB/F000227/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
BB/F020481/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
F/99089 / / British Heart Foundation / United Kingdom
G0601966 / / Medical Research Council / United Kingdom
G0700931 / / Medical Research Council / United Kingdom
G0801056 / / Medical Research Council / United Kingdom
G0901905 / / Medical Research Council / United Kingdom
G9717869 / / Medical Research Council / United Kingdom
SP/04/002 / / British Heart Foundation / United Kingdom