G-Protein β ₃ Subunit Gene (GNB3) 825T Allele Is Associated With Enhanced Renal Perfusion in Early Hypertension

Abstract

Abstract-The C825T polymorphism of the gene encoding the G-protein ␤ 3 subunit (GNB3) is associated with increased intracellular signal transduction and arterial hypertension. The aim of the study was to investigate the impact of this polymorphism on early adaptive processes of the left ventricle and renal hemodynamic changes in young normotensive to mildly hypertensive subjects. Ninety-five white male students with normal or mildly elevated blood pressure were genotyped for the GNB3 C825T polymorphism. In each participant, 24-hour ambulatory blood pressure, left ventricular structure and function (2D-guided M-mode echocardiography), renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (inulin clearance), and 24-hour urinary sodium excretion were determined. The GNB3 825T allele was not associated with casual or ambulatory blood pressure, parameters of left ventricular structure or function, glomerular filtration, or 24-hour urinary sodium excretion. However, in T-allele carriers (CTϩTT), renal plasma flow was higher than in CC subjects (CT/TT: 659Ϯ96 versus CC: 614Ϯ91 mL/min, Pϭ0.019). ANOVA disclosed that renal plasma flow was independently influenced by both genotype and blood pressure, with hypertensives having a higher renal plasma flow than normotensive subjects. This was the fact irrespective of the criteria used for the definition of hypertension (World Health Organization or 24-hour ambulatory blood pressure criteria). The GNB3 825T variant is associated with increased renal perfusion in this study. Because early renal hemodynamic changes play a pivotal role in the pathogenesis of essential hypertension, our data suggest a relevance of increased G-protein activation in the pathogenesis of hypertension. Key Words: G proteins Ⅲ polymorphism Ⅲ genes Ⅲ hypertension, essential Ⅲ hemodynamics T he early course of essential hypertension is characterized by structural and functional changes in the systemic and renal circulation. In addition, early structural changes of the left ventricle (LV) have been reported. Increased concentric remodeling of the LV and impaired diastolic function have been recognized to reflect early changes of the myocardium in early essential hypertension. 1 Renal hemodynamics were shown to be abnormally regulated in a prehypertensive stage, and increased renal perfusion was reported in early hypertension. [2][3][4] It has been proposed that renal vascular changes may not simply be a complication but the cause for blood pressure elevation and thus may play a pivotal role in the pathogenesis of essential hypertension. 5 In the search for mechanisms by which genetic markers contribute to the development of hypertension, recent interest focused on a novel gene polymorphism closely associated with a wellestablished intermediate phenotype, that is, the enhanced Na ϩ /H ϩ exchanger activity in hypertensive subjects. 6 Immortalized lymphoblasts of these patients have been found to respond with enhanced G-protein activation on stimulation. 7 Subsequently, a single nucleo...

G-Protein β 3 -Subunit Gene 825T Allele and Hypertension

“…26,27 In fact, at enrollment, patients with the T allele had higher fasting glucose and lower HDL cholesterol, even if within the normal range. As for the low creatinine levels in patients with the T allele, it must be noted that renal blood and/or plasma flow are normal to enhanced in borderline hypertension and that the 825T allele of the G-protein ␤ 3 -subunit is associated with increased renal plasma flow, 39 and the low creatinine levels may reflect such a renal hemodynamic pattern.…”

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

“…30,31,33,37 Recent studies in rodent cardiomyocytes revealed that b 2 -receptors couple to G-proteins, which lead to inhibition of cyclic AMP formation downstream. 38,39 In the ischaemic myocardium, the Na + /H + exchanger, which itself is under the influence of the C825T polymorphism, 3,4 exerts an important modulatory action on cardiac excitation-contraction coupling. 36 Published studies on the possible influence of the GNB3 C825T polymorphism reported inconsistent results.…”

“…This mutation leads to a gain in function 2 and entails stimulation of the ubiquitously expressed Na + /H + exchanger. 3,4 de la Sierra et al 5 observed that in patients with essential hypertension, left ventricular hypertrophy was associated with increased Na + /H + exchanger activity. In addition, several studies [6][7][8] reported that disorders such as obesity and hypertension, which may cause left ventricular hypertrophy, are associated with the Gprotein b 3 -subunit (GNB3) gene C825T polymorphism.…”

G protein β3 polymorphism and hemodynamic and body composition phenotypes in the HERITAGE Family Study

“…Furthermore, the GNB3 825T allele has been reported to be associated with elevated diastolic blood pressure (DBP) and aldosterone-to-renin ratio and decreased renin and prorenin levels in whites (31), as well as with several intermediate hypertension phenotypes, such as enhanced renal perfusion rate, increased risk of left ventricular hypertrophy, and impaired diastolic filling (21,29,45). Moreover, two studies have reported an association between the GNB3 825T allele and enhanced coronary vasoconstriction (4,25).…”