Combinations of Variations in Multiple Genes Are Associated With Hypertension

Williams, Scott M.; Addy, J.H.; Phillips, John A.; Dai, Min; Kpodonu, John; Afful, James; Jackson, H.; Joseph, K.-K.Li; Eason, Felicia; Murray, Mark M; Epperson, Pamela; Aduonum, Adwoa; Wong, Lee-Jun; José, Pedro A.; Felder, Robin A.

doi:10.1161/01.hyp.36.1.2

Cited by 126 publications

(103 citation statements)

References 24 publications

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“…Genes regulating the renin angiotensin system have been implicated in the pathogenesis of essential hypertension (47,48). In a cohort of Ghanian hypertensive subjects, we found that there was a significant interaction of GRK4 SNPs (termed FJ) with the SNPs of angiotensin converting enzyme, AT 1 angiotensin receptor, and angiotensinogen (49). In a white population, hypertensives (n ϭ 89) and normotensives (n ϭ 90) differed significantly in disease risk as a function of R65L͞A486V haplotypes (unpublished data).…”

Section: Resultsmentioning

confidence: 93%

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

Felder

Sanada

et al. 2002

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

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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: 93%

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

Felder

Sanada

et al. 2002

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

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250

419

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“…Indeed, there is increasing evidence that epistasis or gene-gene interactions play an important role in determining an individual's risk of complex-trait disease. [23][24][25] However, the identification and characterization of gene-gene interactions have been limited by a lack of powerful statistical methods and a lack of large sample sizes. 26 Several new strategies [23][24][25][26][27][28][29][30] have been developed recently to solve these problems.…”

mentioning

confidence: 99%

“…26 Several new strategies [23][24][25][26][27][28][29][30] have been developed recently to solve these problems. Accordingly, we have adopted these methods [23][24][25][26][27][28][29][30] in the present study to explore the multilocus effects of RAS genes on the development of nonfamilial structural AF.…”

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confidence: 99%

Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation

et al. 2004

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Background-The activated local atrial renin-angiotensin system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation (AF). We hypothesized that RAS genes might be among the susceptibility genes of nonfamilial structural AF and conducted a genetic case-control study to demonstrate this. Methods and Results-A total of 250 patients with documented nonfamilial structural AF and 250 controls were selected.The controls were matched to cases on a 1-to-1 basis with regard to age, gender, presence of left ventricular dysfunction, and presence of significant valvular heart disease. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In multilocus haplotype analysis, the angiotensinogen gene haplotype profile was significantly different between cases and controls ( 2 ϭ62.5, Pϭ0.0002). In single-locus analysis, M235T, G-6A, and G-217A were significantly associated with AF. Frequencies of the M235, G-6, and G-217 alleles were significantly higher in cases than in controls (Pϭ0.000, 0.005, and 0.002, respectively). The odds ratios for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3 (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G-217/G-217 genotype. Furthermore, significant gene-gene interactions were detected by the multifactor-dimensionality reduction method and multilocus linkage disequilibrium tests. Conclusions-This study demonstrates the association of RAS gene polymorphisms with nonfamilial structural AF and may provide the rationale for clinical trials to investigate the use of ACE inhibitor or angiotensin II antagonist in the treatment of structural AF.

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“…21 Evidence of gene-gene interaction among effects of polymorphisms in these three genes of the RAA system has been reported with respect to occurrence of HTN. 22 This study is the first to report an association between the combined effects of polymorphisms in the AGT and AT 1 R genes, and BP response to a thiazide diuretic.…”

Section: Discussionmentioning

confidence: 77%

Multilocus effects of the renin–angiotensin–aldosterone system genes on blood pressure response to a thiazide diuretic

Frazier¹,

Turner

Schwartz

et al. 2004

Pharmacogenomics J

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Background: The renin-angiotensin-aldosterone (RAA) system regulates blood pressure (BP) levels and influences responses to antihypertensive medications. Variation in RAA system genes has been reported to influence interindividual differences in BP levels and the occurrence of hypertension (HTN). Methods: We evaluated the relationship between variation in genes of the RAA system and interindividual differences in BP response to a thiazide diuretic. Analyses were carried out in a race-and gender-specific manner in 255 unrelated hypertensive African-Americans (125 men and 130 women) and 246 unrelated hypertensive non-Hispanic Whites (133 men and 113 women). Results: The angiotensin II receptor (AT 1 R) A1166C and angiotensinogen G-6A polymorphisms had a significant effect on systolic BP response to the diuretic in African-American women. Multilocus analyses indicated that the effects of these genes combined additively to influence response. Results of a permutation test to adjust for multiple comparisons and the possible nonindependence among genotypes remained significant at the P ¼ 0.003 level. Conclusions: Among African-American women, particular gene variations in the RAA system have additive effects on BP response to a thiazide diuretic.

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Combinations of Variations in Multiple Genes Are Associated With Hypertension

Cited by 126 publications

References 24 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

Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation

Multilocus effects of the renin–angiotensin–aldosterone system genes on blood pressure response to a thiazide diuretic

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