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

Nature Genetics volume 38, pages 644–651 (2006)Cite this article

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.

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Figure 1: Genome-wide association study of the QT interval.
Figure 2: Genome-wide significance of QTc_RAS.
Figure 3: Fine mapping of the NOS1AP gene.

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Acknowledgements

The authors wish to thank G. Tomaselli, J. Nathans, S. Lin and D.J. Cutler for numerous helpful discussions and D. Levy, E. Benjamin and R. D'Agostino at FHS for contributions to the electrocardiographic QT measurement study. This work was supported in part by the D.W. Reynolds Clinical Cardiovascular Research Center, Johns Hopkins University, the US National Institutes of Health, and the German Federal Ministry of Education and Research (BMBF) both in the context of the program Bioinformatics for the Functional Analysis of Mammalian Genomes (BFAM) and the German National Genome Research Network (NGFN). The authors want to thank H. Löwel, C. Meisinger, R. Holle and J. John from the KORA Study Group. The FHS replication study is a contribution from the Framingham Heart Study of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and Boston University School of Medicine, supported by NHLBI's Framingham Heart Study (Contract No. N01-HC-25195) and the Cardiogenomics Program for Genomic Applications (5U01HL066582), a GlaxoSmithKline Competitive Grants Award Program for Young Investigators (CNC) and NIH (K23HL080025, CNC). Some of the electrocardiographic measurements were supported by an unrestricted grant from Pfizer, Inc.

Author information

Author notes

  1. Dan E Arking and Arne Pfeufer: These authors contributed equally to this work.

Authors and Affiliations

  1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Dan E Arking, Morna Ikeda, Kristen West, Carl Kashuk & Aravinda Chakravarti

  2. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Dan E Arking, Wendy Post, Eduardo Marbán & Peter M Spooner

  3. Institute of Human Genetics, Technical University Munich, Munich, D-81675, Germany

    Arne Pfeufer, Mahmut Akyol, Shapour Jalilzadeh & Thomas Meitinger

  4. Institute of Human Genetics, GSF National Research Center of Environment and Health, Neuherberg, D-85764, Germany

    Arne Pfeufer, Mahmut Akyol, Shapour Jalilzadeh & Thomas Meitinger

  5. Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA

    Wendy Post & W H Linda Kao

  6. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, 01702, Massachusetts, USA

    Christopher Newton-Cheh, Chao-Yu Guo, Martin G Larson & Christopher J O'Donnell

  7. Broad Institute of Harvard and MIT, Cambridge, 02139, Massachusetts, USA

    Christopher Newton-Cheh, Christopher J O'Donnell & Joel N Hirschhorn

  8. Cardiology Division, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Christopher Newton-Cheh & Christopher J O'Donnell

  9. Institute of Medical Informatics, GSF National Research Center of Environment and Health, Neuherberg, D-85764, Germany

    Siegfried Perz

  10. Institute of Epidemiology, GSF National Research Center of Environment and Health, Neuherberg, D-85764, Germany

    Thomas Illig, Christian Gieger & H Erich Wichmann

  11. Department of Mathematics and Statistics, Boston University, Boston, 02215, Massachusetts, USA

    Chao-Yu Guo & Martin G Larson

  12. Institute of Information Management, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, D-81377, Germany

    H Erich Wichmann

  13. Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, 02115, Massachusetts, USA

    Joel N Hirschhorn

  14. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Joel N Hirschhorn

  15. Department of Medicine I, Ludwig-Maximilians-Universität, Munich, D-81377, Germany

    Stefan Kääb

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  1. Dan E Arking
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Corresponding author

Correspondence to Aravinda Chakravarti.

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Competing interests

A.C. is a paid member of the Affymetrix Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Supplementary information

Supplementary Table 1

Summary of stage I results stratified by short and long QT interval. (PDF 90 kb)

Supplementary Table 2

Candidate gene list and SNP coverage on Affymetrix Centurion arrays. (PDF 42 kb)

Supplementary Table 3

Genome-wide association study of QTc_RAS: screening results from stages I and II. (PDF 140 kb)

Supplementary Table 4

Association study of QTc_RAS emphasizing candidate genes assayed genome-wide: screening results from stages I and II. (PDF 140 kb)

Supplementary Table 5

Significance of additional CAPON SNPs in the entire KORA S4 sample. (PDF 137 kb)

Supplementary Table 6

Sequenom SNP primers, probes and conditions. (PDF 65 kb)

Supplementary Table 7

Primers used in sequencing conserved regions in CAPON. (PDF 10 kb)

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Arking, D., Pfeufer, A., Post, W. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 38, 644–651 (2006). https://doi.org/10.1038/ng1790

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