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

作者：Kapoor Ashish; Sekar Rajesh B; Hansen Nancy F; Fox Talbot Karen; Morley Michael; Pihur Vasyl; Chatterjee Sumantra; Brandimarto Jeffrey; Moravec Christine S; Pulit Sara L; Pfeufer Arne; Mullikin Jim; Ross Mark; Green Eric D; Bentley David; Newton Cheh Christopher; Boerwinkle Eric; Tomaselli Gordon F; Cappola Thomas P; Arking Dan E; Halushka Marc K; Chakravarti Aravinda^*

来源：American Journal of Human Genetics, 2014, 94(6): 854-869.

DOI：10.1016/j.ajhg.2014.05.001

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.

• 出版日期2014-6-5
• 单位NIH