Association of alpha1a-adrenergic receptor polymorphism and blood pressure phenotypes in the Brazilian population

Freitas, Sílvia Regina Sampaio; Pereira, Alexandre C.; Floriano, Marcilene S; Mill, José Geraldo; Krieger, José Eduardo

doi:10.1186/1471-2261-8-40

Cited by 22 publications

(14 citation statements)

References 25 publications

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“…This gene has not been represented in any of the large genome-wide meta-analysis of BP, lipids and BMI. Small candidate gene studies have shown nominal association with hypertension in Chinese populations [35,36]. The results of our study are in line with the large whole genome meta-analyses and may indicate that the association we detected is specific for the metabolic syndrome condition.…”

Section: Discussionsupporting

confidence: 93%

Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population

Padmanabhan

Menni

Seravalle

et al. 2011

Journal of Hypertension

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Section: Discussionsupporting

confidence: 93%

Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population

Padmanabhan

Menni

Seravalle

et al. 2011

Journal of Hypertension

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“…The G247R SNP present in the third intracellular loop of the α 1a AR was originally identified in a patient with severe hypertension. Several studies suggest association of α 1a AR genetic variants with human disease, and a few report associations between α 1a AR SNPs and hypertension in humans (14,15).…”

mentioning

confidence: 99%

Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway

Oganesian

Yarov‐Yarovoy

Parks³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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We previously identified a naturally occurring human SNP, G247R, in the third intracellular loop of the α 1a -adrenergic receptor (α 1a -247R) and demonstrated that constitutive expression of α 1a -247R results in twofold increased cell proliferation compared with WT. In the present study we elucidate molecular mechanisms and signal transduction pathways responsible for increased cell proliferation unique to α 1a -247R, but not α 1a -WT, α 1b , or α 1d AR subtypes. We show that elevated levels of matrix metalloproteinase-7 (MMP7) and a disintegrin and metalloproteinase-12 (ADAM12) in α 1a -247R-expressing cells are responsible for EGF receptor (EGFR) transactivation, downstream ERK activation, and increased cell proliferation; this pathway is confirmed using MMP, EGFR, and ERK inhibitors. We demonstrate that EGFR transactivation and downstream ERK activation depends on increased shedding of heparin-binding EGF. Finally, we demonstrate that knockdown of MMP7 or β-arrestin1 by shRNAs results in attenuation of proliferation of cells expressing α 1a -247R. Importantly, accelerated cell proliferation triggered by the α 1a -247R is serum-and agonist-independent, providing unique evidence for constitutive active coupling to the β-arrestin1/MMP/EGFR transactivation pathway by any G protein-coupled receptor. These findings raise the possibility of a previously unexplored mechanism for sympathetically mediated human hypertension triggered by a naturally occurring human genetic variant.

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“…The angiotensin receptor was associated with BP in men only [13]. BP-associated interactions have been reported between body mass index and CYP19A1 Ion channel regulation G protein-coupled receptor kinase 4 (GRK4) [ 192] [ 99] Ion channel regulation/vasoconstriction Adrenergic receptor, beta 2 (ADRB2) [ 135,193] [ 194] Ion channel regulation/vasoconstriction Adrenergic receptor, alpha 1A (ADRA1A) [ 195,196] [ 135,197] Ion channel regulation/vasoconstriction Adrenergic receptor, beta 1 (ADRB1) [ 135,198] [ 199] Ion channel regulation/vasoconstriction Adrenergic receptor, beta 3 (ADRB3) [ inactive individuals who carry the same number of minor alleles of these SNPs.…”

Section: Analysis Of Interactions In Candidate Gene Studiesmentioning

confidence: 99%

Between Candidate Genes and Whole Genomes: Time for Alternative Approaches in Blood Pressure Genetics

2011

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Blood pressure has a significant genetic component, but less than 3% of the observed variance has been attributed to genetic variants identified to date. Candidate gene studies of rare, monogenic hypertensive syndromes have conclusively implicated several genes altering renal sodium balance, and studies of essential hypertension have inconsistently implicated over 50 genes in pathways affecting renal sodium balance and other functions. Genome-wide linkage scans have replicated numerous quantitative trait loci throughout the genome, and over 50 single nucleotide polymorphisms (SNPs) have been replicated in multiple genome-wide association studies. These studies provide considerable evidence that epistasis and other interactions play a role in the genetic architecture of blood pressure regulation, but candidate gene studies have limited scope to test for epistasis, and genome-wide studies have low power for both main effects and interactions. This review summarizes the genetic findings to date for blood pressure, and it proposes focused, pathway-based approaches involving epistasis, gene-environment interactions, and next-generation sequencing to further the genetic dissection of blood pressure and hypertension.

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Association of alpha1a-adrenergic receptor polymorphism and blood pressure phenotypes in the Brazilian population

Cited by 22 publications

References 25 publications

Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population

Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population

Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway

Between Candidate Genes and Whole Genomes: Time for Alternative Approaches in Blood Pressure Genetics

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