title: DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males.
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.
authors.affiliation: Hypertension and Related Diseases Center, Azienda Ospedaliero Universitaria-Università di Sassari, Sassari, Sardinia, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.forename: Victoria L M
authors.initials: VL
authors.lastname: Herrera
authors.forename: Tamara
authors.initials: T
authors.lastname: Didishvili
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Argiolas
authors.forename: Chiara
authors.initials: C
authors.lastname: Troffa
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bulla
authors.forename: Emanuela
authors.initials: E
authors.lastname: Bulla
authors.forename: Nelson
authors.initials: N
authors.lastname: Ruiz-Opazo
mesh_terms: D000368:Aged; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics*; D056726:Genetic Association Studies; D006339:Heart Rate / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011544:Pseudogenes; D019655:Quantitative Trait, Heritable; D011956:Receptors, Cell Surface / Q000235:genetics*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: C571813:FBXW7-AS1 non-coding RNA, human; D011956:Receptors, Cell Surface