Common Variants at SCN5A-SCN10A and HEY2 Are Associated With Brugada Syndrome, a Rare Disease With High Risk of Sudden Cardiac Death

Nat Genet. 2013 Sep;45(9):1044-9. doi: 10.1038/ng.2712. Epub 2013 Jul 21.

Abstract

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Brugada Syndrome / complications*
  • Brugada Syndrome / genetics*
  • Case-Control Studies
  • Chromosomes, Human, Pair 3
  • Chromosomes, Human, Pair 6
  • Death, Sudden, Cardiac / etiology*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • NAV1.8 Voltage-Gated Sodium Channel / genetics*
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Repressor Proteins / genetics*
  • Sodium Channels / genetics
  • Sodium Channels / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HEY2 protein, human
  • NAV1.5 Voltage-Gated Sodium Channel
  • NAV1.8 Voltage-Gated Sodium Channel
  • Repressor Proteins
  • SCN10A protein, human
  • SCN5A protein, human
  • Sodium Channels