Erika Salvi 1 , Zoltán Kutalik , Nicola Glorioso , Paola Benaglio , Francesca Frau , Tatiana Kuznetsova , Hisatomi Arima , Clive Hoggart , Jean Tichet , Yury P Nikitin , Costanza Conti , Jitka Seidlerova , Valérie 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
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.