Genetic variation in SCN10A influences cardiac conduction

J.C. Chambers, J. Zhao, C.M.N. Terracciano, C.R. Bezzina, W. Zhang, R. Kaba, M. Navaratnarajah, A. Lotlikar, J.S. Sehmi, M.K. Kooner, G. Deng, U. Siedlecka, S. Parasramka, I. El-Hamamsy, M.N. Wass, L.R.C. Dekker, J.S.S.G. de Jong, M.J.E. Sternberg, W. McKenna, N.J. SeversR. de Silva, A.A.M. Wilde, P. Anand, M. Yacoub, J. Scott, P. Elliott, J.N. Wood, J.S. Kooner

Research output: Contribution to journalArticleAcademicpeer-review

199 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)149-152
Number of pages4
JournalNature Genetics
Volume42
Issue number2
DOIs
Publication statusPublished - Feb 2010
Externally publishedYes

Keywords

  • Adult
  • 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

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