Document Detail


DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males.
MedLine Citation:
PMID:  21862670     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Essential hypertension is highly prevalent in the elderly population, exceeding 70% in people older than 60 yr of age, and remains a leading risk factor for heart disease, stroke, and chronic renal disease. Elucidation of genetic determinants is critical but remains a challenge due to its complex, multifactorial pathogenesis. We investigated the role DEspR promoter variants, previously associated with male essential hypertension susceptibility, in blood pressure (BP) regulation. We detected a single nucleotide polymorphism within the DEspR 5'-regulatory region associated with increased BP in a male Sardinian cohort accounting for 11.0 mmHg of systolic BP (P<10(-15)) and 9.3 mmHg of diastolic BP (P<10(-15)). Sequence analysis of three normotensive subjects homozygous for the rs6535847 "normotension-associated T-allele" identified a canonical TATAAAA-box in contrast to a CATAAAA-motif in three hypertensive subjects homozygous for the rs6535847 "hypertension-associated C-allele." In vitro analysis detected decreased transcription activity with the CATAAAA-motif promoter-construct compared with the canonical TATAAAA-box promoter-construct. Although BP did not differ between DEspR+/- knockout male mice and wild-type littermates at 6 mo of age, radiotelemetric BP measurements in 18 mo old inbred DEspR+/- knockout male mice known to have decreased DEspR RNA and protein detected higher systolic, mean, and diastolic BPs in DEspR+/- mice compared with littermate wild-type controls (P<0.05). Our results demonstrate that promoter variants in DEspR associated with hypertension susceptibility and increased BP in Sardinian males affect transcription levels, which then affect BP in an age-dependent and male-specific manner. This finding is concordant with the late-onset and sex-specific characteristics of essential hypertension, thus reiterating the mandate for sex-specific analyses and treatment approaches for essential hypertension.
Authors:
Nicola Glorioso; Victoria L M Herrera; Tamara Didishvili; Giuseppe Argiolas; Chiara Troffa; Patrizia Bulla; Emanuela Bulla; Nelson Ruiz-Opazo
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-23
Journal Detail:
Title:  Physiological genomics     Volume:  43     ISSN:  1531-2267     ISO Abbreviation:  Physiol. Genomics     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-08     Completed Date:  2012-05-04     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  9815683     Medline TA:  Physiol Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1219-25     Citation Subset:  IM    
Affiliation:
Hypertension and Related Diseases Center, Azienda Ospedaliero Universitaria-Università di Sassari, Sassari, Sardinia, Italy.
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MeSH Terms
Descriptor/Qualifier:
Aged
Animals
Base Sequence
Blood Pressure / genetics*
Genetic Association Studies
Heart Rate / genetics
Heterozygote
Humans
Italy
Male
Mice
Molecular Sequence Data
Nucleotide Motifs / genetics
Polymerase Chain Reaction
Polymorphism, Single Nucleotide / genetics*
Promoter Regions, Genetic / genetics*
Quantitative Trait, Heritable
Receptors, Cell Surface / genetics*
Transcription Initiation Site
Transcription, Genetic*
Grant Support
ID/Acronym/Agency:
HL-98939/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DEspR protein, human; 0/Receptors, Cell Surface
Comments/Corrections

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