Target sequencing, cell experiments, and a population study establish endothelial nitric oxide synthase (eNOS) gene as hypertension susceptibility gene.

Details

Serval ID
serval:BIB_09900E0CC53A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Target sequencing, cell experiments, and a population study establish endothelial nitric oxide synthase (eNOS) gene as hypertension susceptibility gene.
Journal
Hypertension
Author(s)
Salvi E., Kuznetsova T., Thijs L., Lupoli S., Stolarz-Skrzypek K., D'Avila F., Tikhonoff V., De Astis S., Barcella M., Seidlerová J., Benaglio P., Malyutina S., Frau F., Velayutham D., Benfante R., Zagato L., Title A., Braga D., Marek D., Kawecka-Jaszcz K., Casiglia E., Filipovsky J., Nikitin Y., Rivolta C., Manunta P., Beckmann J.S., Barlassina C., Cusi D., Staessen J.A.
ISSN
1524-4563 (Electronic)
ISSN-L
0194-911X
Publication state
Published
Issued date
2013
Volume
62
Number
5
Pages
844-852
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
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.
Keywords
Adult, Alleles, Blood Pressure/genetics, Case-Control Studies, Endothelium, Vascular/physiopathology, European Continental Ancestry Group/genetics, Female, Genetic Predisposition to Disease, Genotype, Humans, Hypertension/genetics, Hypertension/physiopathology, Male, Middle Aged, Nitric Oxide Synthase Type III/genetics, Polymorphism, Single Nucleotide, Promoter Regions, Genetic
Pubmed
Open Access
Yes
Create date
15/02/2015 20:38
Last modification date
20/08/2019 12:31
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