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An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval.

TitleAn enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval.
Publication TypeJournal Article
Year of Publication2014
AuthorsKapoor A, Sekar RB, Hansen NF, Fox-Talbot K, Morley M, Pihur V, Chatterjee S, Brandimarto J, Moravec CS, Pulit SL, Pfeufer A, Mullikin J, Ross M, Green ED, Bentley D, Newton-Cheh C, Boerwinkle E, Tomaselli GF, Cappola TP, Arking DE, Halushka MK
Secondary AuthorsChakravarti A
Corporate AuthorsQT Interval-International GWAS Consortium
JournalAm J Hum Genet
Date Published2014 Jun 05
KeywordsAdaptor Proteins, Signal Transducing, Animals, Cohort Studies, Electrocardiography, Gene Expression Regulation, Genome-Wide Association Study, Genotype, HEK293 Cells, Humans, Lentivirus, Long QT Syndrome, Mice, Myocytes, Cardiac, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Zebrafish

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.

Alternate JournalAm J Hum Genet
PubMed ID24857694
PubMed Central IDPMC4121472
Grant ListR01 GM104469 / GM / NIGMS NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01HL105993 / HL / NHLBI NIH HHS / United States
R01 HL105993 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States