Genetic modifier of the QTc interval associated with early-onset atrial fibrillation.
BACKGROUND
Both shortening and prolongation of the QTc interval have been associated with atrial fibrillation (AF). We investigated whether 8 single nucleotide polymorphisms (SNPs) at loci previously shown to affect QTc interval duration were associated with lone AF.


METHODS
We included 358 patients diagnosed with lone AF (defined as onset of AF at < 50 years of age in the absence of traditional cardiovascular risk factors) and a control group consisting of 751 individuals free of AF. The 8 loci were genotyped using TaqMan assays. Genotype frequencies in lone AF cases and controls were compared using an additive logistic regression model.


RESULTS
Risk of the development of early-onset lone AF in individuals homozygous for the variant rs2968863 (7q36.1) was higher than in individuals with no copies of the risk allele (odds ratio [OR], 2.40; P = 0.001). The association was also significant after Bonferroni correction (P = 0.016). This polymorphism has been shown to decrease the QTc interval by 1.4 ms in genome-wide association studies (GWAS). The genetic variant is situated close to the long QT syndrome (LQTS) type 2 gene KCNH2 that encodes the potassium channel Kv11.1 (hERG). Sanger sequencing of KCNH2 confirmed the known high linkage disequilibrium between rs2968863 and the nonsynonymous variant K897T in KCNH2. No novel mutations were found in the gene.


CONCLUSIONS
The variant rs2968863 (7q36.1), reported in GWAS to shorten the QTc interval, was found to be associated with early-onset lone AF. This may have implications for the pathophysiological understanding of AF.
Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Rigshospitalet, Copenhagen, Denmark; The Ion Channel Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Laura
L
Andreasen
Jonas B
JB
Nielsen
Ingrid E
IE
Christophersen
Anders Gaarsdal
AG
Holst
Ahmad
A
Sajadieh
Arnljot
A
Tveit
Stig
S
Haunsø
Jesper H
JH
Svendsen
Nicole
N
Schmitt
Morten S
MS
Olesen
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D003718:Denmark / Q000453:epidemiology; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D055815:Young Adult
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D004247:DNA