Single nucleotide polymorphisms in proximity to K-channel genes are associated with decreased longitudinal QTc variance.
BACKGROUND
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Despite significant progress in identification of predisposing factors, the pathophysiology of AF remains to be elucidated. Previous studies have reported that single nucleotide polymorphisms (SNPs) in potassium-channel genes associate with AF and the instantaneous corrected QT interval (QTc). The purpose of this study was to examine the association between SNPs in proximity to KCNQ1, KCNH2, KCNE2, and KCNJ2 and longitudinal QTc variations in patients with AF.


RESULTS
We conducted a retrospective cohort study of 800 electrocardiograms from 93 patients with AF. All patients were Caucasian, with an average age of 61.2 years, and 72% were male. Of all patients, 37% had persistent AF, and 63% had paroxysmal AF. Following DNA extraction from blood, SNPs at the AF-associated loci KCNQ1, KCNH2, KCNE2, and KCNJ2 were genotyped using the Sequenom MassARRAY. Using a linear regression model and adapting a resampling inference, a decrease in longitudinal QTc variance was found to associate with SNPs near KCNH2 (rs10240738) and KCNJ2 (rs8079702) when adjusted for patient age, gender, AF type, and average QTc. On average, patients with these SNPs had a shorter QTc interval. In addition, we fitted a multilevel mixed effects regression model accounting for subject level heterogeneity and found no longitudinal association between presence of SNPs near K-channel genes and changes in QTc.


CONCLUSIONS
Polymorphisms near specific potassium-channel genes in AF patients are associated with decreased longitudinal QTc variance and a shorter average QTc. These results support the hypothesis that effects on myocardial repolarization may mediate the association of these SNPs and AF.
The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Yuliya
Y
Mints
Vadim
V
Zipunnikov
Irfan
I
Khurram
Hugh
H
Calkins
Saman
S
Nazarian
D017677:Age Distribution; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology*; D015331:Cohort Studies; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000379:methods / Q000706:statistics & numerical data; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D012189:Retrospective Studies; D017678:Sex Distribution
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; C489457:KCNJ2 protein, human; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated
QT interval; atrial fibrillation; gene polymorphism; potassium channels