Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in us white community-based populations

W. H.Linda Kao, Dan E. Arking, Wendy Post, Thomas D. Rea, Nona Sotoodehnia, Ronald J. Prineas, Bryan Bishe, Betty Q. Doan, Eric Boerwinkle, Bruce M. Psaty, Gordon F. Tomaselli, Josef Coresh, David S. Siscovick, Eduardo Marbán, Peter M. Spooner, Gregory L. Burke, Aravinda Chakravarti

Research output: Contribution to journalArticle

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Abstract

Background-The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs 10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOSlAP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOSlAP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study. Methods and Results-We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs 10494366 and rs4657139 in NOSIAP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOSlAP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs 12567209, which was not correlated with rs 16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs 16847548 and SCD, and such adjustment had no effect on the association between rs 12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOSlAP and either QT interval or SCD were observed in blacks. Conclusions-In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOSlAP were associated with baseline QT interval and the risk of SCD in white US adults.

Original languageEnglish (US)
Pages (from-to)940-951
Number of pages12
JournalCirculation
Volume119
Issue number7
DOIs
StatePublished - Feb 24 2009
Externally publishedYes

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Sudden Cardiac Death
Nitric Oxide Synthase
Population
Proteins
Single Nucleotide Polymorphism
Confidence Intervals
Nitric Oxide Synthase Type I
Genome-Wide Association Study
Proportional Hazards Models
Coronary Disease
Linear Models
Atherosclerosis
Electrocardiography
Cohort Studies
Alleles
Prospective Studies
Ligands
Health

Keywords

  • Arrhythmia
  • Death
  • Epidemiology
  • Genetics
  • Sudden

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in us white community-based populations. / Kao, W. H.Linda; Arking, Dan E.; Post, Wendy; Rea, Thomas D.; Sotoodehnia, Nona; Prineas, Ronald J.; Bishe, Bryan; Doan, Betty Q.; Boerwinkle, Eric; Psaty, Bruce M.; Tomaselli, Gordon F.; Coresh, Josef; Siscovick, David S.; Marbán, Eduardo; Spooner, Peter M.; Burke, Gregory L.; Chakravarti, Aravinda.

In: Circulation, Vol. 119, No. 7, 24.02.2009, p. 940-951.

Research output: Contribution to journalArticle

Kao, WHL, Arking, DE, Post, W, Rea, TD, Sotoodehnia, N, Prineas, RJ, Bishe, B, Doan, BQ, Boerwinkle, E, Psaty, BM, Tomaselli, GF, Coresh, J, Siscovick, DS, Marbán, E, Spooner, PM, Burke, GL & Chakravarti, A 2009, 'Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in us white community-based populations', Circulation, vol. 119, no. 7, pp. 940-951. https://doi.org/10.1161/CIRCULATIONAHA.108.791723
Kao, W. H.Linda ; Arking, Dan E. ; Post, Wendy ; Rea, Thomas D. ; Sotoodehnia, Nona ; Prineas, Ronald J. ; Bishe, Bryan ; Doan, Betty Q. ; Boerwinkle, Eric ; Psaty, Bruce M. ; Tomaselli, Gordon F. ; Coresh, Josef ; Siscovick, David S. ; Marbán, Eduardo ; Spooner, Peter M. ; Burke, Gregory L. ; Chakravarti, Aravinda. / Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in us white community-based populations. In: Circulation. 2009 ; Vol. 119, No. 7. pp. 940-951.
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abstract = "Background-The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs 10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOSlAP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOSlAP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study. Methods and Results-We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs 10494366 and rs4657139 in NOSIAP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOSlAP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95{\%} confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs 12567209, which was not correlated with rs 16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95{\%} confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs 16847548 and SCD, and such adjustment had no effect on the association between rs 12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOSlAP and either QT interval or SCD were observed in blacks. Conclusions-In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOSlAP were associated with baseline QT interval and the risk of SCD in white US adults.",
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T1 - Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in us white community-based populations

AU - Kao, W. H.Linda

AU - Arking, Dan E.

AU - Post, Wendy

AU - Rea, Thomas D.

AU - Sotoodehnia, Nona

AU - Prineas, Ronald J.

AU - Bishe, Bryan

AU - Doan, Betty Q.

AU - Boerwinkle, Eric

AU - Psaty, Bruce M.

AU - Tomaselli, Gordon F.

AU - Coresh, Josef

AU - Siscovick, David S.

AU - Marbán, Eduardo

AU - Spooner, Peter M.

AU - Burke, Gregory L.

AU - Chakravarti, Aravinda

PY - 2009/2/24

Y1 - 2009/2/24

N2 - Background-The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs 10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOSlAP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOSlAP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study. Methods and Results-We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs 10494366 and rs4657139 in NOSIAP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOSlAP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs 12567209, which was not correlated with rs 16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs 16847548 and SCD, and such adjustment had no effect on the association between rs 12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOSlAP and either QT interval or SCD were observed in blacks. Conclusions-In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOSlAP were associated with baseline QT interval and the risk of SCD in white US adults.

AB - Background-The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs 10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOSlAP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOSlAP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study. Methods and Results-We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs 10494366 and rs4657139 in NOSIAP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOSlAP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs 12567209, which was not correlated with rs 16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs 16847548 and SCD, and such adjustment had no effect on the association between rs 12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOSlAP and either QT interval or SCD were observed in blacks. Conclusions-In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOSlAP were associated with baseline QT interval and the risk of SCD in white US adults.

KW - Arrhythmia

KW - Death

KW - Epidemiology

KW - Genetics

KW - Sudden

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