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Updated: May 3, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Single nucleotide polymorphisms in proximity to K-channel genes are associated with decreased longitudinal QTc
Yuliya Mints1, Vadim Zipunnikov, Irfan Khurram
1The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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.
Methods And 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.
Conclusion:
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.
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Comparing Copy Number Variations and SNPs
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...

