Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase

Erika Salvi; Zoltan Kutalik; Nicola Glorioso; Paola Benaglio; Francesca Frau; Tatiana Kuznetsova; Hisatomi Arima; Clive Hoggart; Jean Tichet; Yury P. Nikitin; Costanza Conti; Jitka Seidlerova; Valerie Tikhonoff; Katarzyna Stolarz-Skrzypek; Toby Johnson; Nabila Devos; Laura Zagato; Simonetta Guarrera; Roberta Zaninello; Andrea Calabria; Benedetta Stancanelli; Chiara Troffa; Lutgarde Thijs; Federica Rizzi; Galina Simonova; Sara Lupoli; Giuseppe Argiolas; Daniele Braga; Maria C. D'Alessio; Maria F. Ortu; Fulvio Ricceri; Maurizio Mercurio; Patrick Descombes; Maurizio Marconi; John Chalmers; Stephen Harrap; Jan Filipovsky; Murielle Bochud; Licia Iacoviello; Justine Ellis; Alice V. Stanton; Maris Laan; Sandosh Padmanabhan; Anna F. Dominiczak; Nilesh J. Samani; Olle Melander; Xavier Jeunemaitre; Paolo Manunta; Amnon Shabo; Paolo Vineis; Francesco P. Cappuccio; Mark J. Caulfield; Giuseppe Matullo; Carlo Rivolta; Patricia B. Munroe; Cristina Barlassina; Jan A. Staessen; Jacques S. Beckmann; Daniele Cusi

doi:10.1161/HYPERTENSIONAHA.111.181990

Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase

Erika Salvi, Zoltan Kutalik, Nicola Glorioso, Paola Benaglio, Francesca Frau, Tatiana Kuznetsova, Hisatomi Arima, Clive Hoggart, Jean Tichet, Yury P. Nikitin, Costanza Conti, Jitka Seidlerova, Valerie Tikhonoff, Katarzyna Stolarz-Skrzypek, Toby Johnson, Nabila Devos, Laura Zagato, Simonetta Guarrera, Roberta Zaninello, Andrea CalabriaBenedetta Stancanelli, Chiara Troffa, Lutgarde Thijs, Federica Rizzi, Galina Simonova, Sara Lupoli, Giuseppe Argiolas, Daniele Braga, Maria C. D'Alessio, Maria F. Ortu, Fulvio Ricceri, Maurizio Mercurio, Patrick Descombes, Maurizio Marconi, John Chalmers, Stephen Harrap, Jan Filipovsky, Murielle Bochud, Licia Iacoviello, Justine Ellis, Alice V. Stanton, Maris Laan, Sandosh Padmanabhan, Anna F. Dominiczak, Nilesh J. Samani, Olle Melander, Xavier Jeunemaitre, Paolo Manunta, Amnon Shabo, Paolo Vineis, Francesco P. Cappuccio, Mark J. Caulfield, Giuseppe Matullo, Carlo Rivolta, Patricia B. Munroe, Cristina Barlassina, Jan A. Staessen, Jacques S. Beckmann, Daniele Cusi^*

^*Corresponding author for this work

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

Abstract

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P = 2.58 . 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P = 1.032 . 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus. (Hypertension. 2012; 59: 248-255.). Online Data Supplement

Original language	English
Pages (from-to)	248–255
Journal	Hypertension
Volume	59
Issue number	2
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.111.181990
Publication status	Published - Feb 2012

Keywords

genetic epidemiology
risk factors
genetics association studies
NO
essential hypertension

Access to Document

10.1161/HYPERTENSIONAHA.111.181990

Cite this

Salvi, E., Kutalik, Z., Glorioso, N., Benaglio, P., Frau, F., Kuznetsova, T., Arima, H., Hoggart, C., Tichet, J., Nikitin, Y. P., Conti, C., Seidlerova, J., Tikhonoff, V., Stolarz-Skrzypek, K., Johnson, T., Devos, N., Zagato, L., Guarrera, S., Zaninello, R., ... Cusi, D. (2012). Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase. Hypertension, 59(2), 248–255. https://doi.org/10.1161/HYPERTENSIONAHA.111.181990

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title = "Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase",

abstract = "Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P = 2.58 . 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P = 1.032 . 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus. (Hypertension. 2012; 59: 248-255.). Online Data Supplement",

keywords = "genetic epidemiology, risk factors, genetics association studies, NO, essential hypertension",

author = "Erika Salvi and Zoltan Kutalik and Nicola Glorioso and Paola Benaglio and Francesca Frau and Tatiana Kuznetsova and Hisatomi Arima and Clive Hoggart and Jean Tichet and Nikitin, {Yury P.} and Costanza Conti and Jitka Seidlerova and Valerie Tikhonoff and Katarzyna Stolarz-Skrzypek and Toby Johnson and Nabila Devos and Laura Zagato and Simonetta Guarrera and Roberta Zaninello and Andrea Calabria and Benedetta Stancanelli and Chiara Troffa and Lutgarde Thijs and Federica Rizzi and Galina Simonova and Sara Lupoli and Giuseppe Argiolas and Daniele Braga and D'Alessio, {Maria C.} and Ortu, {Maria F.} and Fulvio Ricceri and Maurizio Mercurio and Patrick Descombes and Maurizio Marconi and John Chalmers and Stephen Harrap and Jan Filipovsky and Murielle Bochud and Licia Iacoviello and Justine Ellis and Stanton, {Alice V.} and Maris Laan and Sandosh Padmanabhan and Dominiczak, {Anna F.} and Samani, {Nilesh J.} and Olle Melander and Xavier Jeunemaitre and Paolo Manunta and Amnon Shabo and Paolo Vineis and Cappuccio, {Francesco P.} and Caulfield, {Mark J.} and Giuseppe Matullo and Carlo Rivolta and Munroe, {Patricia B.} and Cristina Barlassina and Staessen, {Jan A.} and Beckmann, {Jacques S.} and Daniele Cusi",

year = "2012",

month = feb,

doi = "10.1161/HYPERTENSIONAHA.111.181990",

language = "English",

volume = "59",

pages = "248–255",

journal = "Hypertension",

issn = "0194-911X",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "2",

}

Salvi, E, Kutalik, Z, Glorioso, N, Benaglio, P, Frau, F, Kuznetsova, T, Arima, H, Hoggart, C, Tichet, J, Nikitin, YP, Conti, C, Seidlerova, J, Tikhonoff, V, Stolarz-Skrzypek, K, Johnson, T, Devos, N, Zagato, L, Guarrera, S, Zaninello, R, Calabria, A, Stancanelli, B, Troffa, C, Thijs, L, Rizzi, F, Simonova, G, Lupoli, S, Argiolas, G, Braga, D, D'Alessio, MC, Ortu, MF, Ricceri, F, Mercurio, M, Descombes, P, Marconi, M, Chalmers, J, Harrap, S, Filipovsky, J, Bochud, M, Iacoviello, L, Ellis, J, Stanton, AV, Laan, M, Padmanabhan, S, Dominiczak, AF, Samani, NJ, Melander, O, Jeunemaitre, X, Manunta, P, Shabo, A, Vineis, P, Cappuccio, FP, Caulfield, MJ, Matullo, G, Rivolta, C, Munroe, PB, Barlassina, C, Staessen, JA, Beckmann, JS & Cusi, D 2012, 'Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase', Hypertension, vol. 59, no. 2, pp. 248–255. https://doi.org/10.1161/HYPERTENSIONAHA.111.181990

Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase. / Salvi, Erika; Kutalik, Zoltan; Glorioso, Nicola et al.
In: Hypertension, Vol. 59, No. 2, 02.2012, p. 248–255.

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

TY - JOUR

T1 - Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase

AU - Salvi, Erika

AU - Kutalik, Zoltan

AU - Glorioso, Nicola

AU - Benaglio, Paola

AU - Frau, Francesca

AU - Kuznetsova, Tatiana

AU - Arima, Hisatomi

AU - Hoggart, Clive

AU - Tichet, Jean

AU - Nikitin, Yury P.

AU - Conti, Costanza

AU - Seidlerova, Jitka

AU - Tikhonoff, Valerie

AU - Stolarz-Skrzypek, Katarzyna

AU - Johnson, Toby

AU - Devos, Nabila

AU - Zagato, Laura

AU - Guarrera, Simonetta

AU - Zaninello, Roberta

AU - Calabria, Andrea

AU - Stancanelli, Benedetta

AU - Troffa, Chiara

AU - Thijs, Lutgarde

AU - Rizzi, Federica

AU - Simonova, Galina

AU - Lupoli, Sara

AU - Argiolas, Giuseppe

AU - Braga, Daniele

AU - D'Alessio, Maria C.

AU - Ortu, Maria F.

AU - Ricceri, Fulvio

AU - Mercurio, Maurizio

AU - Descombes, Patrick

AU - Marconi, Maurizio

AU - Chalmers, John

AU - Harrap, Stephen

AU - Filipovsky, Jan

AU - Bochud, Murielle

AU - Iacoviello, Licia

AU - Ellis, Justine

AU - Stanton, Alice V.

AU - Laan, Maris

AU - Padmanabhan, Sandosh

AU - Dominiczak, Anna F.

AU - Samani, Nilesh J.

AU - Melander, Olle

AU - Jeunemaitre, Xavier

AU - Manunta, Paolo

AU - Shabo, Amnon

AU - Vineis, Paolo

AU - Cappuccio, Francesco P.

AU - Caulfield, Mark J.

AU - Matullo, Giuseppe

AU - Rivolta, Carlo

AU - Munroe, Patricia B.

AU - Barlassina, Cristina

AU - Staessen, Jan A.

AU - Beckmann, Jacques S.

AU - Cusi, Daniele

PY - 2012/2

Y1 - 2012/2

N2 - Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P = 2.58 . 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P = 1.032 . 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus. (Hypertension. 2012; 59: 248-255.). Online Data Supplement

AB - Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P = 2.58 . 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P = 1.032 . 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus. (Hypertension. 2012; 59: 248-255.). Online Data Supplement

KW - genetic epidemiology

KW - risk factors

KW - genetics association studies

KW - NO

KW - essential hypertension

U2 - 10.1161/HYPERTENSIONAHA.111.181990

DO - 10.1161/HYPERTENSIONAHA.111.181990

M3 - Article

C2 - 22184326

SN - 0194-911X

VL - 59

SP - 248

EP - 255

JO - Hypertension

JF - Hypertension

IS - 2

ER -

Salvi E, Kutalik Z, Glorioso N, Benaglio P, Frau F, Kuznetsova T et al. Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase. Hypertension. 2012 Feb;59(2):248–255. doi: 10.1161/HYPERTENSIONAHA.111.181990