In:
Physiological Genomics, American Physiological Society, Vol. 43, No. 21 ( 2011-11), p. 1219-1225
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1094-8341
,
1531-2267
DOI:
10.1152/physiolgenomics.00012.2011
Language:
English
Publisher:
American Physiological Society
Publication Date:
2011
detail.hit.zdb_id:
2031330-5
