Association of the α-Adducin Locus With Essential Hypertension

Casari, Giorgio; Barlassina, Cristina; Cusi, Daniele; Zagato, Laura; Muirhead, Roslyn; Righetti, Marco; Nembri, P; Amar, Karen; Gatti, Mauro; Macciardi, Fabìo; Binelli, Giorgio; Bianchi, Giuseppe

doi:10.1161/01.hyp.25.3.320

Cited by 146 publications

(75 citation statements)

References 43 publications

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“…However, the GRK4 locus is linked with essential hypertension (29). Sequencing of GRK4 cDNAs from normotensive and hypertensive subjects confirmed the presence of SNPs (24): nucleotide 448, CGT to CTT (amino acid R65L) and the two reported variants, nucleotide 679, GCC to GTC (amino acid A142V), and nucleotide 1711, GCG to GTG (amino acid A486V).…”

Section: Resultsmentioning

confidence: 90%

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Felder

Sanada

et al. 2002

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

247

419

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Essential hypertension has a heritability as high as 30 -50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D1 dopamine receptor and the G protein͞effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4␥, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein͞effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4␥A142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. These findings provide a mechanism for the D1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.L ong-term regulation of blood pressure is vested in the organ responsible for the control of body fluid volume, the kidney (1, 2). Dopamine facilitates the antihypertensive function of the kidney because it is both vasodilatory and natriuretic (3). Dopamine (produced by renal proximal tubules) via D 1 -like receptors is responsible for over 50% of incremental sodium excretion when sodium intake is increased (3-6). The paracrine͞ autocrine dopaminergic regulation of sodium excretion is mediated by tubular but not by hemodynamic mechanisms (6). The ability of dopamine and D 1 -like agonists to decrease renal proximal tubular sodium reabsorption is impaired in genetic rodent hypertension and human essential hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15). Indeed, the aberrant D 1 -like receptor function in the kidney precedes and cosegregates with high blood pressure in spontaneously hypertensive rats. In addition, disruption of the D 1 receptor in mice produces hypertension (12, 13). The pivotal role of dopamine in the excretion of sodium after increased sodium intake has led to the hypothesis that an aberrant renal dopaminergic system is important in the pathogenesis of some forms of genetic hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Several mechanisms potentially responsible for the failure of endogenous renal dopamine to engender a natriuretic effect in genetic hypertension have been investigated and ruled out, including decreased renal dopamine production and receptor expression, aberrant nephron segment distribution of dopamine receptors, defective effector enzymes (adenylyl cyclase or...

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Section: Resultsmentioning

confidence: 90%

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Felder

Sanada

et al. 2002

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

247

419

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“…9 Transfection studies with cDNA from the MHS showed altered ability of adducin to interact with actin and increased maximum velocity of the sodium-potassium pump. 18 In humans, polymorphic markers flanking the ␣-adducin gene have been shown to be associated with primary hypertension in Italians 19 and linkage has been demonstrated between the ␣-adducin locus and primary hypertension in French families. 20 The tryptophane variant of a polymorphism in the ␣-adducin gene which codes for either glycine or tryptophane at codon 460 (Gly460Trp) has been associated with hypertension in Italian, French and Japanese populations.…”

Section: Introductionmentioning

confidence: 99%

Role of the Gly460Trp polymorphism of the α-adducin gene in primary hypertension in Scandinavians

et al. 2000

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Previous studies have suggested that the Trp460 allele of the Gly460Trp polymorphism in the ␣-adducin gene is associated with salt sensitivity and primary hypertension. The present study was undertaken to evaluate if the Trp460 allele of this polymorphism is associated with primary hypertension in Scandinavians. To address this issue, 294 patients with primary hypertension and 265 normotensive control subjects from Sweden were examined and genotyped for the Gly460Trp polymorphism using polymerase chain reaction and restriction fragment length polymorphism methods. We then used a population of 80 patients with primary hypertension and 154 normotensive control subjects from Finland to replicate the findings. The frequency of the Trp460 allele was lower in hypertensive patients than in normotensive controls in the Swedish population (17.7% vs 23.0%; P ‫؍‬ 0.03) and in the Finnish population (14.4% vs 19.5%; NS). Therefore we also performed a pooled analysis in

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“…1 The recognition that genetic factors are involved in the pathogenesis of hypertension is derived from studies comparing the blood pressures of monozygotic and dizygotic twins, 2 from epidemiologic studies of familial aggregation of hypertension, 3 and from studies comparing blood pressures among biologic and adoptive siblings. 4 Some genetic variants, such as polymorphisms in the angiotensinogen 5,6 and ␣-adducin 7,8 genes, can increase the risk for hypertension, but the full spectrum of genes that contribute to this condition are poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women

et al. 1999

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Genes that can be implicated in hypertension in experimental animals are plausible candidates in the pathogenesis of human hypertension. A recent genome-wide search for quantitative-trait loci (QTL) in hypertensive rats revealed a strong correlation between the interleukin-6 (IL-6) locus on rat chromosome 4 and systolic, diastolic, and mean arterial pressure in this mammalian species. To investigate a possible association between genetic variations of the IL-6 gene and hypertension in humans, we identified two novel single-nucleotide sequence variations, a C/G substitution at −634 in the promoter region and a G/A substitution at 4391 in a 3 ′ non-coding portion of exon 5, and a previous reported sequence variant, an A/T variation in the composition of the A n T n tract around −447 in the promoter region ( Fishman D et al. J Clin Invest 1998; 102: 1369-1376, within a test population of 96 Japanese subjects. Allelic associations involving these variations were analyzed in 150 hypertensive and 143 normotensive Japanese women. The distribution of alleles of the three polymorphisms, as well as a dinucleotide repeat present at the IL-6 locus, was similar in the two groups. Therefore, the IL-6 gene appears to play a minimal role in the genetic etiology of essential hypertension in Japanese women.

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Association of the α-Adducin Locus With Essential Hypertension

Cited by 146 publications

References 43 publications

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Role of the Gly460Trp polymorphism of the α-adducin gene in primary hypertension in Scandinavians

Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women

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