Background: Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the primary diseasecausing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTScausative gene, AKAP9, for potential LQTS-type 1-modifying effects.Methods and Results: Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001).Conclusions: AKAP9 has been identified as an LQTS-type 1-modifying gene. Variants investigated altered heart rate-corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.
de Villiers, C., van der Merwe, L., Crotti, L., Goosen, A., George, A., Schwartz, P., et al. (2014). AKAP9 is a genetic modifier of congenital long-QT syndrome type 1. CIRCULATION, CARDIOVASCULAR GENETICS, 7(5), 599-606 [10.1161/CIRCGENETICS.113.000580].
|Citazione:||de Villiers, C., van der Merwe, L., Crotti, L., Goosen, A., George, A., Schwartz, P., et al. (2014). AKAP9 is a genetic modifier of congenital long-QT syndrome type 1. CIRCULATION, CARDIOVASCULAR GENETICS, 7(5), 599-606 [10.1161/CIRCGENETICS.113.000580].|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Presenza di un coautore afferente ad Istituzioni straniere:||Si|
|Titolo:||AKAP9 is a genetic modifier of congenital long-QT syndrome type 1|
|Autori:||de Villiers, C; van der Merwe, L; Crotti, L; Goosen, A; George, A; Schwartz, P; Brink, P; Moolman- Smook, J; Corfield, V|
|Data di pubblicazione:||2014|
|Rivista:||CIRCULATION, CARDIOVASCULAR GENETICS|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1161/CIRCGENETICS.113.000580|
|Appare nelle tipologie:||01 - Articolo su rivista|