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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)854-869
Number of pages16
JournalAmerican journal of human genetics
Volume94
Issue number6
DOIs
StatePublished - Jun 5 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Kapoor, A., Sekar, R. B., Hansen, N. F., Fox-Talbot, K., Morley, M., Pihur, V., Chatterjee, S., Brandimarto, J., Moravec, C. S., Pulit, S. L., Pfeufer, A., Mullikin, J., Ross, M., Green, E. D., Bentley, D., Newton-Cheh, C., Boerwinkle, E., Tomaselli, G. F., Cappola, T. P., ... Chakravarti, A. (2014). An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval. American journal of human genetics, 94(6), 854-869. https://doi.org/10.1016/j.ajhg.2014.05.001