A case-control study revealed association between hypertension and rs3918226 in the endothelial nitric oxide synthase (eNOS) gene promoter (minor/major allele, T/C allele). We aimed at substantiating these preliminary findings by target sequencing, cell experiments, and a population study. We sequenced the 140-kb genomic area encompassing the eNOS gene. In HeLa and HEK293T cells transfected with the eNOS promoter carrying either the T or the C allele, we quantified transcription by luciferase assay. In 2722 randomly recruited Europeans (53.0% women; mean age 40.1 years), we studied blood pressure change and incidence of hypertension in relation to rs3918226, using multivariable-adjusted models. Sequencing confirmed rs3918226, a binding site of E-twenty six transcription factors, as the single nucleotide polymorphism most closely associated with hypertension. In T compared with C transfected cells, eNOS promoter activity was from 20% to 40% (P<0.01) lower. In the population, systolic/diastolic blood pressure increased over 7.6 years (median) by 9.7/6.8 mm Hg in 28 TT homozygotes and by 3.8/1.9 mm Hg in 2694 C allele carriers (P≤0.0004). The blood pressure rise was 5.9 mm Hg systolic (confidence interval [CI], 0.6-11.1; P=0.028) and 4.8 mm Hg diastolic (CI, 1.5-8.2; P=0.0046) greater in TT homozygotes, with no differences between the CT and CC genotypes (P≥0.90). Among 2013 participants normotensive at baseline, 692 (34.4%) developed hypertension. The hazard ratio and attributable risk associated with TT homozygosity were 2.04 (CI, 1.24-3.37; P=0.0054) and 51.0%, respectively. In conclusion, rs3918226 in the eNOS promoter tags a hypertension susceptibility locus, TT homozygosity being associated with lesser transcription and higher risk of hypertension.
Target sequencing, cell experiments, and a population study establish endothelial nitric oxide synthase (eNOS) gene as hypertension susceptibility gene / E. Salvi, T. Kuznetsova, L. Thijs, S. Lupoli, K. Stolarz-Skrzypek, F. D'Avila, V. Tikhonoff, S. De Astis, M. Barcella, J. Seidlerová, P. Benaglio, S. Malyutina, F. Frau, D. Velayutham, R. Benfante, L. Zagato, A. Title, D. Braga, D. Marek, K. Kawecka-Jaszcz, E. Casiglia, J. Filipovsky, Y. Nikitin, C. Rivolta, P. Manunta, J.S. Beckmann, C. Barlassina, D. Cusi, J.A. Staessen. - In: HYPERTENSION. - ISSN 0194-911X. - 62:5(2013 Nov), pp. 844-852.
|Titolo:||Target sequencing, cell experiments, and a population study establish endothelial nitric oxide synthase (eNOS) gene as hypertension susceptibility gene|
SALVI, ERIKA (Primo)
BARLASSINA, MARIA CRISTINA (Ultimo)
CUSI, DANIELE MARIA (Corresponding)
|Parole Chiave:||blood pressure; endothelial nitric oxide synthase gene; hypertension; population science; target sequencing; transfection|
|Settore Scientifico Disciplinare:||Settore MED/14 - Nefrologia|
|Data di pubblicazione:||nov-2013|
|Data ahead of print / Data di stampa:||9-set-2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01428|
|Appare nelle tipologie:||01 - Articolo su periodico|