title: Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death.
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.
authors.affiliation: Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands. c.r.bezzina@amc.uva.nl
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authors.identifier: 0000000277227348
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authors.identifier: 0000000177512280
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mesh_terms: D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D053840:Brugada Syndrome / Q000150:complications* / Q000235:genetics*; D016022:Case-Control Studies; D002893:Chromosomes, Human, Pair 3; D002896:Chromosomes, Human, Pair 6; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D012097:Repressor Proteins; D015222:Sodium Channels; C405693:HEY2 protein, human; C568317:SCN10A protein, human; C568320:SCN5A protein, human