Authors

Erika Salvi, University of Milano, Italy
Zoltán Kutalik, University of Lausanne, Switzerland
Nicola Glorioso, University of Sassari, Italy
Paola Benaglio, University of Lausanne, Switzerland
Francesca Frau, University of Milano, Italy
Tatiana Kuznetsova, University of Leuven, Belgium
Hisatomi Arima, University of Sydney and the Royal Prince Alfred Hospital
Clive Hoggart, Imperial College of London
Jean Tichet, Institut inter Régional pour la Santé, France
Yury P. Nikitin, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russian Federation
Costanza Conti, I.M.S., Milano, Italy
Jitka Seidlerova, Charles University, Czech Republic
Valérie Tikhonoff, University of Padova, Italy
Katarzyna Stolarz-Skrzypek, Jagiellonian University Medical College, Poland
Toby Johnson, Queen Mary University of London, UK
Nabila Devos, INSERM, France
Laura Zagato, San Raffaele Scientific Institute, Italy
Simonetta Guarrera, Human Genetics Foundation (HUGEF), Italy
Roberta Zaninello, University of Sassari, Italy
Andrea Calabria, University of Milano, Italy
Benedetta Stancanelli, University of Catania, Italy
Chiara Troffa, University of Sassari, Italy
Lutgarde Thijs, University of Leuven, Belgium
Federica Rizzi, KOS Genetic, Italy
Galina Simonova, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russian Federation
Sara Lupoli, University of Milano, Italy
Giuseppe Argiolas, University of Sassari, Italy
Daniele Braga, KOS Genetic, Italy
Maria C. D'Alessio, I.M.S., Milano, Italy
Maria F. Ortu, University of Sassari, Italy
Fulvio Ricceri, University of Torino and Human Genetics Foundation
Maurizio Mercurio, KOS Genetic, Italy
Patrick Descombes, University of Geneva, Switzerland
Maurizio Marconi, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy
John Chalmers, University of Sydney and the Royal Prince Alfred Hospital
Stephen Harrap, University of Melbourne Australia
Jan Filipovsky, Charles University, Czech Republic
Murielle Bochud, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Switzerland
Licia Iacoviello, Catholic University, Italy
Justine Ellis, University of Melbourne, Australia
Alice V. Stanton, Royal College of Surgeons in Ireland
Maris Laan, University of Tartu, Estonia
Sandosh Padmanabhan
Anna F. Dominiczak, University of Glasgow, UK
Nilesh J. Samani, University of Leicester, UK
Olle Melander, Lund University, Sweden
Xavier Jeunemaitre, INSERM, France
Paolo Manunta, San Raffaele Scientific Institute, Italy
Amnon Shabo, Haifa University, Israel
Paolo Vineis, Imperial College of London
Francesco P. Cappuccio, University of Warwick, UK
Mark J. Caulfield, Queen Mary University of London, UK
Giuseppe Matullo, University of Torino and Human Genetics Foundation
Carlo Rivolta, University of Lausanne, Switzerland
Patricia B. Munroe, Queen Mary University of London, UK
Cristina Barlassina, University of Milano, Italy
Jan A. Staessen, University of Leuven, Belgium
Jacques S Beckmann, University of Lausanne, Switzerland
Daniele Cusi, University of Milano, Italy

Document Type

Article

Publication Date

2-2012

Comments

This article is also available at http://hyper.ahajournals.org/content/59/2/248.long

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.

Disciplines

Life Sciences

Citation

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. 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):248-55.

PubMed ID

22184326

DOI Link

10.1161/​HYPERTENSIONAHA.111.181990

Included in

Life Sciences Commons

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