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Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death
- Source :
- Nature genetics, 45(9), 1044-1049. Nature Publishing Group
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
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.
- Subjects :
- Male
Qrs Duration
Bioinformatics
Sodium Channels
NAV1.5 Voltage-Gated Sodium Channel
Sudden cardiac death
Genome-Wide Association
Mice
Atrial Gene-Expression
Basic Helix-Loop-Helix Transcription Factors
Odds Ratio
Brugada Syndrome
Brugada syndrome
Mice, Knockout
St-Segment Elevation
SECS-S/01 - STATISTICA
cardiovascular system
Cardiology
Chromosomes, Human, Pair 6
Female
Chromosomes, Human, Pair 3
medicine.medical_specialty
Bundle-Branch Block
BIO/18 - GENETICA
Locus (genetics)
Biology
Polymorphism, Single Nucleotide
Article
NAV1.8 Voltage-Gated Sodium Channel
Internal medicine
Genetic variation
Cardiac conduction
Genetics
medicine
Animals
Humans
Genetic Predisposition to Disease
cardiovascular diseases
HEY2
Alleles
Heart-Rate
Genetic Variation
Cardiac arrhythmia
MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE
medicine.disease
Qt Interval Duration
Repressor Proteins
Ventricular-Fibrillation
Pr Interval
Death, Sudden, Cardiac
Case-Control Studies
Conduction System
Genome-Wide Association Study
Rare disease
Subjects
Details
- ISSN :
- 15461718 and 10614036
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- Nature Genetics
- Accession number :
- edsair.doi.dedup.....8578dbbe2ed8dd464bb8685a62569057