An Enhancer Polymorphism at the Cardiomyocyte Intercalated Disc Protein NOS1AP Locus Is a Major Regulator of the QT Interval

Abstract

QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.

Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential

“…However, despite the rapid pace of discovery, relatively few studies have directly linked a genetic variant at a locus to plausible biological mechanism for disease. 36–42 For AF, at least 30 loci have been identified to date, yet the underlying molecular mechanism at most of these loci remains incompletely understood. In the present work, we have used an integrative functional genomics approach that combines resequencing of the candidate locus, phenotypic modeling in both zebrafish and stem cell derived cardiomyocytes, chromatin conformation analyses, the identification of gene regulatory elements, and eQTL mapping to elucidate a functional variant at the 1q24 locus for AF.…”

The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity

“…1,2 Yet, the understanding of how these genetic associations modulate cardiac electrophysiology has been limited to only a few loci. 3,4 As for most GWAS signals, those associated with electrophysiological traits are located in noncoding regulatory regions 5 and are expected to affect or indirect, by modulating expression of transcription factors, which themselves regulate ion channel gene expression. We previously identified a locus at 6q22.31 associated with Brugada syndrome (BrS)-an inherited disease associated with increased risk of ventricular arrhythmias and sudden cardiac death in young individuals.…”

Pharmacogenetics of Potassium Channel Blockers

“…24 The mechanism of the association has not been definitively established but NOS1AP has been reported to modulate sodium, potassium, and calcium channel function. 25,26 The advantage of this approach that entirely new modulators of human traits may be identified, as in the case of NOS1AP and the QT. However, while these associations are highly statistically significant, each SNP contributes a very small amount to the trait under study.…”