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 Kääb; Peter M. Spooner; Thomas Meitinger; Aravinda Chakravarti

doi:10.1038/ng1790

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 Kääb

Peter M. Spooner, Thomas Meitinger, Aravinda Chakravarti

Medicine and Health

Johns Hopkins School of Medicine
Technical University of Munich
Helmholtz Zentrum München German Research Center for Environmental Health
Johns Hopkins Bloomberg School of Public Health
Framingham Heart Study
The Broad Institute of MIT and Harvard
Massachusetts General Hospital
Boston University
University of Munich
Boston Children's Hospital
Harvard Medical School

Research output: Contribution to journal › Article › peer-review

470 Scopus citations

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 language	English
Pages (from-to)	644-651
Number of pages	8
Journal	Nature Genetics
Volume	38
Issue number	6
DOIs	https://doi.org/10.1038/ng1790
State	Published - Jun 2006

Access to Document

10.1038/ng1790

Cite this

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

@article{72ba5bfc72d34a8a9f5ca03b81269254,

title = "A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization",

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.",

author = "Arking, \{Dan E.\} and Arne Pfeufer and Wendy Post and Kao, \{W. H.Linda\} and Christopher Newton-Cheh and Morna Ikeda and Kristen West and Carl Kashuk and Mahmut Akyol and Siegfried Perz and Shapour Jalilzadeh and Thomas Illig and Christian Gieger and Guo, \{Chao Yu\} and Larson, \{Martin G.\} and Wichmann, \{H. Erich\} and Eduardo Marb{\'a}n and O'Donnell, \{Christopher J.\} and Hirschhorn, \{Joel N.\} and Stefan K{\"a}{\"a}b and Spooner, \{Peter M.\} and Thomas Meitinger and Aravinda Chakravarti",

note = "Funding Information: 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. L{\"o}wel, 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{\textquoteright}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.",

year = "2006",

month = jun,

doi = "10.1038/ng1790",

language = "English",

volume = "38",

pages = "644--651",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Arking, DE, Pfeufer, A, Post, W, Kao, WHL, Newton-Cheh, C, Ikeda, M, West, K, Kashuk, C, Akyol, M, Perz, S, Jalilzadeh, S, Illig, T, Gieger, C, Guo, CY, Larson, MG, Wichmann, HE, Marbán, E, O'Donnell, CJ, Hirschhorn, JN, Kääb, S, Spooner, PM, Meitinger, T & Chakravarti, A 2006, 'A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization', Nature Genetics, vol. 38, no. 6, pp. 644-651. https://doi.org/10.1038/ng1790

TY - JOUR

T1 - A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization

AU - Arking, Dan E.

AU - Pfeufer, Arne

AU - Post, Wendy

AU - Kao, W. H.Linda

AU - Newton-Cheh, Christopher

AU - Ikeda, Morna

AU - West, Kristen

AU - Kashuk, Carl

AU - Akyol, Mahmut

AU - Perz, Siegfried

AU - Jalilzadeh, Shapour

AU - Illig, Thomas

AU - Gieger, Christian

AU - Guo, Chao Yu

AU - Larson, Martin G.

AU - Wichmann, H. Erich

AU - Marbán, Eduardo

AU - O'Donnell, Christopher J.

AU - Hirschhorn, Joel N.

AU - Kääb, Stefan

AU - Spooner, Peter M.

AU - Meitinger, Thomas

AU - Chakravarti, Aravinda

N1 - Funding Information: 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.

PY - 2006/6

Y1 - 2006/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/33745237158

U2 - 10.1038/ng1790

DO - 10.1038/ng1790

M3 - Article

C2 - 16648850

AN - SCOPUS:33745237158

SN - 1061-4036

VL - 38

SP - 644

EP - 651

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this