Association Study of G Protein‐Coupled Receptor Kinase 4 Gene Variants with Essential Hypertension in Northern Han Chinese

Wang, Yaping; Li, Biao; Zhao, Weiyan; Liu, Pei; Zhao, Qi; Chen, Shufeng; Li, Hongfan; Gu, Dongfeng

doi:10.1111/j.1469-1809.2006.00278.x

Cited by 32 publications

(19 citation statements)

References 13 publications

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“…An Australian group confirmed the association between the Val142 GRK4 polymorphism and essential hypertension in a case-control study of 168 Caucasian hypertensive subjects and 312 normotensive controls (296). A case control study of ϳ1,000 Chinese showed an association between the GRK4 position 486 polymorphism and essential hypertension (110,326). In contrast, a study from the Netherlands found no association between the GRK4 Ala142Val polymorphism and blood pressure or renal sodium excretion (299).…”

Section: Grk Polymorphismsmentioning

confidence: 83%

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Dorn

2010

Physiological Reviews

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This review examines the impact of recent discoveries defining personal genetics of adrenergic signaling polymorphisms on scientific discovery and medical practice related to cardiovascular diseases. The adrenergic system is the major regulator of minute-by-minute cardiovascular function. Inhibition of adrenergic signaling with pharmacological beta-adrenergic receptor antagonists (beta-blockers) is first-line therapy for heart failure and hypertension. Advances in pharmacology, molecular biology, and genetics of adrenergic signaling pathways have brought us to the point where personal genetic differences in adrenergic signaling factors are being assessed as determinants of risk or progression of cardiovascular disease. For a few polymorphisms, functional data generated in cell-based systems, genetic mouse models, and pharmacological provocation of human subjects are concordant with population studies that suggest altered risk of cardiovascular disease or therapeutic response to beta-blockers. For the majority of adrenergic pathway polymorphisms however, published data conflict, and the clinical relevance of individual genotyping remains uncertain. Here, the current state of laboratory and clinical evidence that adrenergic pathway polymorphisms can affect cardiovascular pathophysiology is comprehensively reviewed and compared, with a goal of placing these data in the broad context of potential clinical applicability.

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Section: Grk Polymorphismsmentioning

confidence: 83%

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Dorn

2010

Physiological Reviews

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“…Furthermore, GRK4 single nucleotide polymorphisms have been previously reported and include R65L, A142V, and A486V. GRK4-A486V has been associated with hypertension in Italian patients (15), in Chinese patients (267), and in an Australian cohort of patients (234). Although in these three studies no association between hypertension and GRK4-R65L or GRK4-A142V variant was seen, increasing copies of GRK4-R65L and GRK4-A142V were associated with reduced atenolol-induced diastolic blood pressure lowering (256).…”

Section: B Grk4 and Grk6 In Hypertensionmentioning

confidence: 99%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

126

152

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G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

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“…43 In another study, GRK4 486V is associated with hypertension in Italian subjects, 44 reminiscent of the phenotype of the human GRK4 486V transgenic mice. 36 In a study of northern Han Chinese subjects, the GRK4 65L, 142V, and A486 haplotypes are associated with a 6-fold higher risk of systolic and diastolic hypertension 45 (Table 2). In another report of the same Han Chinese data from the same group, the A486V polymorphism is also shown to be associated with hypertension, but the allele that increased the risk is 486V.…”

Section: Grk4 Polymorphisms and Hypertensionmentioning

confidence: 99%

G Protein–Coupled Receptor Kinase 4

Zeng

Villar²,

Eisner³

et al. 2008

Hypertension

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N early 30% of middle-aged Americans have hypertension, but the prevalence is higher in non-Hispanic blacks and individuals Ͼ60 years of age (65%). 1 There is a direct and quantitative relationship between higher blood pressure values and mortality. Although 30% to 50% is thought to be heritable, the genetic cause(s) of essential hypertension has been difficult to identify. More than 1 gene is undoubtedly involved, because Mendelian dominant and recessive traits are not readily discernible in hypertensive subjects, except in those with monogenic forms of hypertension. Moreover, in any hypertensive individual, risk-predisposing genes are engaged in a complex network of gene-gene and geneenvironment interactions. 2,3 The kidney plays a major role in the long-term regulation of blood pressure, and abnormal sodium chloride metabolism is frequently encountered in hypertension. Therefore, many studies have focused on the abnormal renal handling of sodium chloride in the pathogenesis of essential hypertension. 2,4 Approximately 50% of subjects with essential hypertension are sodium chloride sensitive. 5 Indeed, humans with salt-sensitive hypertension have increased sodium transport in the renal proximal tubule and medullary thick ascending limb, although distal tubular mechanisms may also be involved. 6 The sodium retention in hypertension is because of enhanced sodium transport, per se, and/or a failure to respond appropriately to signals that decrease sodium transport. Sodium transport is regulated by natriuretic and antinatriuretic hormones and humoral agents, such as dopamine and angiotensin, which exert their effects via G protein-coupled receptors (GPCRs). Activation of certain postjunctional dopamine receptor subtypes (D 1 R, D 3 R, D 4 R, and D 5 R) and the angiotensin type 2 receptor inhibit, whereas activation of the postjunctional D 2 R and angiotensin type 1 receptor (AT 1 R) increase sodium transport. 2,7 GPCR Kinase FamilyThe GPCR kinases (GRKs) are a 7-member family of serine/threonine protein kinases characterized by their ability to phosphorylate or modify and desensitize agonist-occupied cell surface membrane GPCRs. GRKs 1 and 7 belong to the rhodopsin family; GRKs 2 and 3 belong to the ␤-adrenergic receptor kinase family, and GRKs 4, 5, and 6 belong to the GRK4 family (Table 1). GRKs 1 and 7 are expressed exclusively in rods and cones, respectively, in the retina. GRKs 2, 3, 5, and 6 are ubiquitously expressed, whereas GRK4 expression is limited (see below). 8 Overexpression of GRK2, GRK3, and especially GRK5 in human embryonic kidney cells desensitizes the D 1 R. 9 GRK activity and GRK2 expression are increased in lymphocytes of patients with essential hypertension and spontaneously hypertensive rats (SHRs). 10 Overexpression of GRK2 in vascular smooth muscles in mice produces hypertension and impairs the vasodilatory action of ␤-adrenergic receptors. 11 The vasoconstrictor response to angiotensin II is also impaired in these mice, which is at odds with the increased reactivity and sensitivity to an...

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Association Study of G Protein‐Coupled Receptor Kinase 4 Gene Variants with Essential Hypertension in Northern Han Chinese

Cited by 32 publications

References 13 publications

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

Adrenergic Signaling Polymorphisms and Their Impact on Cardiovascular Disease

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

G Protein–Coupled Receptor Kinase 4

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