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
Authors: Salvi, Erika
Kutalik, Zoltán
Glorioso, Nicola
Benaglio, Paola
Frau, Francesca
Kuznetsova, Tatiana
Arima, Hisatomi
Hoggart, Clive
Tichet, Jean
Nikitin, Yury P
Conti, Costanza
Seidlerova, Jitka
Tikhonoff, Valérie
Stolarz-Skrzypek, Katarzyna
Johnson, Toby
Devos, Nabila
Zagato, Laura
Guarrera, Simonetta
Zaninello, Roberta
Calabria, Andrea
Stancanelli, Benedetta
Troffa, Chiara
Thijs, Lutgarde
Rizzi, Federica
Simonova, Galina
Lupoli, Sara
Argiolas, Giuseppe
Braga, Daniele
D'Alessio, Maria C
Ortu, Maria F
Ricceri, Fulvio
Mercurio, Maurizio
Descombes, Patrick
Marconi, Maurizio
Chalmers, John
Harrap, Stephen
Filipovsky, Jan
Bochud, Murielle
Iacoviello, Licia
Ellis, Justine
Stanton, Alice V
Laan, Maris
Padmanabhan, Sandosh
Dominiczak, Anna F
Samani, Nilesh J
Melander, Olle
Jeunemaitre, Xavier
Manunta, Paolo
Shabo, Amnon
Vineis, Paolo
Cappuccio, Francesco P
Caulfield, Mark J
Matullo, Giuseppe
Rivolta, Carlo
Munroe, Patricia B
Barlassina, Cristina
Staessen, Jan A
Beckmann, Jacques S
Cusi, Daniele # ×
Issue Date: Feb-2012
Publisher: Lippincott Williams & Wilkins
Series Title: Hypertension vol:59 issue:2 pages:248-255
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.
ISSN: 0194-911X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Hypertension and Cardiovascular Epidemiology
× corresponding author
# (joint) last author

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