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

Nature Genetics 38, 644–651 (2006) | Download Citation

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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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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

    • Dan E Arking
    •  & Arne Pfeufer

    These authors contributed equally to this work.

Affiliations

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

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

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

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

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

    • Arne Pfeufer
    • , Mahmut Akyol
    • , Shapour Jalilzadeh
    •  & Thomas Meitinger

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

    • Arne Pfeufer
    • , Mahmut Akyol
    • , Shapour Jalilzadeh
    •  & Thomas Meitinger

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

    • Wendy Post
    •  & W H Linda Kao

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

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

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

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

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

    • Christopher Newton-Cheh
    •  & Christopher J O'Donnell

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

    • Siegfried Perz

  10. Institute of Epidemiology, GSF National Research Center of Environment and Health, D-85764 Neuherberg, 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, D-81377 Munich, 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, Massachusetts 02115, USA.

    • Joel N Hirschhorn

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

    • Stefan Kääb

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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.

Corresponding author

Correspondence to Aravinda Chakravarti.

Supplementary information

PDF files

  1. 1.

    Supplementary Table 1

    Summary of stage I results stratified by short and long QT interval.

  2. 2.

    Supplementary Table 2

    Candidate gene list and SNP coverage on Affymetrix Centurion arrays.

  3. 3.

    Supplementary Table 3

    Genome-wide association study of QTc_RAS: screening results from stages I and II.

  4. 4.

    Supplementary Table 4

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

  5. 5.

    Supplementary Table 5

    Significance of additional CAPON SNPs in the entire KORA S4 sample.

  6. 6.

    Supplementary Table 6

    Sequenom SNP primers, probes and conditions.

  7. 7.

    Supplementary Table 7

    Primers used in sequencing conserved regions in CAPON.

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DOI

https://doi.org/10.1038/ng1790

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