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 - Tập 59 Số 2 - Trang 248-255 - 2012
Erika Salvi1, Zoltán Kutalik1, Nicola Glorioso1, Paola Benaglio1, Francesca Frau1, Tatiana Kuznetsova1, Hisatomi Arima1, Clive Hoggart1, Jean Tichet1, Nikitin IuP1, Costanza Conti1, Jitka Seidlerová1, Valérie Tikhonoff1, Katarzyna Stolarz‐Skrzypek1, Toby Johnson1, Nabila Devos1, Laura Zagato1, Simonetta Guarrera1, Roberta Zaninello1, Andrea Calabria1, Benedetta Stancanelli1, Chiara Troffa1, Lutgarde Thijs1, Federica Rizzi1, Г. И. Симонова1, Sara Lupoli1, Giuseppe Argiolas1, Daniele Braga1, Maria C. D'Alessio1, Maria Francesca Ortu1, Fulvio Ricceri1, Maurizio Mercurio1, Patrick Descombes1, Maurizio Marconi1, John Chalmers1, Stephen Harrap1, Jan Filipovský1, Murielle Bochud1, Licia Iacoviello1, Justine A. Ellis1, Alice Stanton1, Maris Laan1, Sandosh Padmanabhan1, Anna F. Dominiczak1, Nilesh J. Samani1, Olle Melander1, Xavier Jeunemaı̂tre1, Paolo Manunta1, Amnon Shabo1, Paolo Vineis1, Francesco P. Cappuccio1, Mark J. Caulfield1, Giuseppe Matullo1, Carlo Rivolta1, Patricia B. Munroe1, Cristina Barlassina1, Jan A. Staessen1, J. Beckmann1, Daniele Cusi1
1From the Department of Medicine, Surgery, and Dentistry (E.S., F.F., A.C., S.L., C.B., D.C.), Graduate School of Nephrology, University of Milano, Division of Nephrology, San Paolo Hospital, Milano, Italy; Filarete Foundation (E.S., F.F., A.C., S.L., C.B., D.C.), Genomic and Bioinformatics Unit, Milano, Italy; Department of Medical Genetics (Z.K., P.B., C.R., J.S.B.), University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics (Z.K.), Lausanne, Switzerland; Hypertension and...

Tóm tắt

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.

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Hypertension

Tập 59 Số 2

248-255

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