Candidate gene approach to identifying rare genetic variants associated with lone atrial fibrillation.
Heart Rhythm
; 11(1): 46-52, 2014 Jan.
Article
em En
| MEDLINE
| ID: mdl-24120998
ABSTRACT
BACKGROUND:
Rare variants in candidate atrial fibrillation (AF) genes have been associated with AF in small kindreds. The extent to which such polymorphisms contribute to AF is unknown.OBJECTIVE:
The purpose of this study was to determine the spectrum and prevalence of rare amino acid coding (AAC) variants in candidate AF genes in a large cohort of unrelated lone AF probands.METHODS:
We resequenced 45 candidate genes in 303 European American (EA) lone AF probands (186 lone AF probands screened for each gene on average [range 89-303], 63 screened for all) identified in the Vanderbilt AF Registry (2002-2012). Variants detected were screened against 4300 EAs from the Exome Sequencing Project (ESP) to identify very rare (minor allele frequency ≤0.04%) AAC variants and these were tested for AF co-segregation in affected family members where possible.RESULTS:
Median age at AF onset was 46.0 years [interquartile range 33.0-54.0], and 35.6% had a family history of AF. Overall, 63 very rare AAC variants were identified in 60 of 303 lone AF probands, and 10 of 19 (52.6%) had evidence of co-segregation with AF. Among the 63 lone AF probands who had 45 genes screened, the very rare variant burden was 22%. Compared with the 4300 EA ESP, the proportion of lone AF probands with a very rare AAC variant in CASQ2 and NKX2-5 was increased 3-5-fold (P <.05).CONCLUSION:
No very rare AAC variants were identified in ~80% of lone AF probands. Potential reasons for the lack of very rare AAC variants include a complex pattern of inheritance, variants in as yet unidentified AF genes or in noncoding regions, and environmental factors.Palavras-chave
AAC; AF; Atrial fibrillation arrhythmia; BMI; Candidate genes; ECG; ESP; Exome Sequencing Project; Family study; GWAS; Genetic epidemiology; Genetic variation; IQR; LVEDD; LVEF; LVESD; MAF; Proarrhythmia; Rare variants; SNP; amino acid coding; atrial fibrillation; body mass index; electrocardiogram; genome-wide association study; interquartile range; left ventricular ejection fraction; left ventricular end-diastolic diameter; left ventricular end-systolic diameter; minor allele frequency; single nucleotide polymorphism
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
2_ODS3
Base de dados:
MEDLINE
Assunto principal:
Fibrilação Atrial
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Variação Genética
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Sistema de Registros
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Polimorfismo de Nucleotídeo Único
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Estudos de Associação Genética
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Heart Rhythm
Ano de publicação:
2014
Tipo de documento:
Article