Genetic variation in SCN10A influences cardiac conduction

Nat Genet. 2010 Feb;42(2):149-52. doi: 10.1038/ng.516. Epub 2010 Jan 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Asian Continental Ancestry Group / genetics
  • Chromosomes, Human, Pair 3 / genetics
  • Electrocardiography
  • Europe
  • Female
  • Genetic Loci / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study
  • Heart Block / complications
  • Heart Block / genetics
  • Heart Block / physiopathology
  • Heart Conduction System / physiology*
  • Heart Rate / genetics
  • Humans
  • India
  • Male
  • Mice
  • Middle Aged
  • NAV1.8 Voltage-Gated Sodium Channel
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide / genetics
  • Reproducibility of Results
  • Sodium Channels / deficiency
  • Sodium Channels / genetics*
  • Telemetry
  • Ventricular Fibrillation / complications
  • Ventricular Fibrillation / genetics
  • Ventricular Fibrillation / physiopathology

Substances

  • NAV1.8 Voltage-Gated Sodium Channel
  • SCN10A protein, human
  • Scn10a protein, mouse
  • Sodium Channels