Variants in Genes Involved in Functional Pathways Associated with Hypertension in African Americans

Cantarin, Maria P. Martinez; Ertel, Adam; DeLoach, Stephanie; Fortina, Paolo; Scott, Kathryn; Burns, Trudy L.; Falkner, Bonita

doi:10.1111/j.1752-8062.2010.00242.x

Cited by 20 publications

(16 citation statements)

References 44 publications

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“…[43]. There is also a report of a negative association of the A486V SNP and hypertension in African Americans, although this study did also see some signal for hypertension with the R65L SNP, in association with NOS3 polymorphisms [44]. In contrast, studies in patients of European ancestry failed to find association with either SNP A142V or A486V [45] [46].…”

Section: Introductionmentioning

confidence: 79%

Abnormalities in renal dopamine signaling and hypertension

Harris

2012

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of review This review will highlight recent findings concerning the role of the intrarenal dopaminergic system in hypertension, especially the role of alterations in GRK4 activity. Recent findings Recent studies highlight the importance of the intrarenal dopaminergic system in blood pressure regulation and how defects in dopamine signaling are involved in the development of hypertension. There are recent experimental models that definitively demonstrate that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. Furthermore, studies in experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II AT1 receptor activity and are associated with essential hypertension in a number of different human cohorts. Summary The ongoing elucidation of this important regulatory pathway further emphasizes the importance of the kidney in maintenance of blood pressure control and may help to delineate underlying mechanisms predisposing individuals or populations to increased risk for development of hypertension.

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Section: Introductionmentioning

confidence: 79%

Abnormalities in renal dopamine signaling and hypertension

Harris

2012

Current Opinion in Nephrology &Amp; Hypertension

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“…In addition to the above-mentioned human studies, no single site GRK4 polymorphism showed significant association with hypertension in a population from Ghana (275). Yet, in another study, GRK4-A486V has also been implicated with hypertension, as has R65L, but only when in conjunction with other polymorphisms (156). To clarify discrepancies, meta-analysis of all five human studies was recently conducted and subgroup analysis by ethnicity revealed that GRK4-A486V inversely correlated with hypertension among East Asians, while it positively correlates among Europeans.…”

Section: B Grk4 and Grk6 In Hypertensionmentioning

confidence: 88%

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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“…The first cohort included 412 young AA adults aged 18–49 years [18] and the second cohort included 300 AA youth aged 12–19 years [19]. A total of 38 AA male cases (SBP≥140 mmHg or DBP≥90 mmHg with or without medication) and 38 age (±2 years) and BMI (normal/overweight/obese) matched male controls (SBP<120 mmHg and DBP<80 mmHg) were selected from the young adult cohort and 6 AA male EH cases (SBP≥140 mmHg) and 6 age (±2 years) and BMI (normal/overweight/obese) matched controls (SBP<110 mmHg and DBP<70 mmHg) were selected from the youth cohort.…”

Section: Methodsmentioning

confidence: 99%

A Genome-Wide Methylation Study on Essential Hypertension in Young African American Males

et al. 2013

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ObjectiveThere is emerging evidence from animal studies suggesting a key role for methylation in the pathogenesis of essential hypertension. However, to date, very few studies have investigated the role of methylation in the development of human hypertension, and none has taken a genome-wide approach. Based on the recent studies that highlight the involvement of inflammation in the development of hypertension, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of hypertension.Method & ResultsWe conducted a genome-wide methylation analysis on 8 hypertensive cases and 8 normotensive age-matched controls aged 14–23 years and performed validation of the most significant CpG sites in 2 genes in an independent sample of 36 hypertensive cases and 60 normotensive controls aged 14–30 years. Validation of the CpG sites in the SULF1 gene was further conducted in a second replication sample of 36 hypertensive cases and 34 controls aged 15.8–40 years. A CpG site in the SULF1 gene showed higher methylation levels in cases than in healthy controls in the genome-wide step (p = 6.2×10−5), which was confirmed in the validation step (p = 0.011) for subjects ≤30 years old but was not significant for subjects of all ages combined (p = 0.095).ConclusionThe identification of a difference in a blood leukocyte DNA methylation site between hypertensive cases and normotensive controls suggests that changes in DNA methylation may play an important role in the pathogenesis of hypertension. The age dependency of the effect further suggests complexity of epigenetic regulation in this age-related disease.

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Variants in Genes Involved in Functional Pathways Associated with Hypertension in African Americans

Cited by 20 publications

References 44 publications

Abnormalities in renal dopamine signaling and hypertension

Abnormalities in renal dopamine signaling and hypertension

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

A Genome-Wide Methylation Study on Essential Hypertension in Young African American Males

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