A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization

Dan E. Arking, Arne Pfeufer, Wendy Post, W. H.Linda Kao, Christopher Newton-Cheh, Morna Ikeda, Kristen West, Carl Kashuk, Mahmut Akyol, Siegfried Perz, Shapour Jalilzadeh, Thomas Illig, Christian Gieger, Chao Yu Guo, Martin G. Larson, H. Erich Wichmann, Eduardo Marbán, Christopher J. O'Donnell, Joel N. Hirschhorn, Stefan KääbPeter M. Spooner, Thomas Meitinger, Aravinda Chakravarti

Research output: Contribution to journalArticle

Abstract

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

Original languageEnglish (US)
Pages (from-to)644-651
Number of pages8
JournalNature genetics
Volume38
Issue number6
DOIs
StatePublished - Jun 1 2006

ASJC Scopus subject areas

  • Genetics

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    Arking, D. E., Pfeufer, A., Post, W., Kao, W. H. L., Newton-Cheh, C., Ikeda, M., West, K., Kashuk, C., Akyol, M., Perz, S., Jalilzadeh, S., Illig, T., Gieger, C., Guo, C. Y., Larson, M. G., Wichmann, H. E., Marbán, E., O'Donnell, C. J., Hirschhorn, J. N., ... Chakravarti, A. (2006). A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nature genetics, 38(6), 644-651. https://doi.org/10.1038/ng1790