Relationships among endogenous ouabain, alpha-adducin polymorphisms and renal sodium handling in primary hypertension.

OBJECTIVE: The basolateral Na pump drives renotubular reabsorption. In cultured renal cells, mutant adducins, as well as sub-nanomolar ouabain concentrations, stimulate the Na-K pump. METHODS: To determine whether these factors interact and affect Na handling and blood pressure (BP) in vivo, we studied 155 untreated hypertensive patients subdivided on the basis of their plasma endogenous ouabain or alpha-adducin genotype (ADD1 Gly460Trp-rs4961). RESULTS: Under basal conditions, proximal tubular reabsorption and plasma Na were higher in patients with mutated Trp ADD1 or increased endogenous ouabain (P = 0.002 and 0.05, respectively). BPs were higher in the high plasma endogenous ouabain group (P = 0.001). Following volume loading, the increment in BP (7.73 vs. 4.81 mmHg) and the slopes of the relationship between BP and Na excretion were greater [0.017 +/- 0.002 vs. 0.009 +/- 0.003 mmHg/(muEq min)] in ADD1 Trp vs. ADD1 Gly carriers (P < 0.05). BP changes were similar, whereas the slopes of the relationship between BP and Na excretion were lower [0.016 +/- 0.003 vs. 0.008 +/- 0.002 mmHg/(muEq min)] in patients with low vs. high endogenous ouabain (P < 0.05). In patients with high endogenous ouabain, volume loading increased the BP in the ADD1 Trp group but not in the Gly group (P < 0.05). Thus, patients with ADD1 Trp alleles are sensitive to salt and tubular Na reabsorption remains elevated after volume expansion. CONCLUSION: With saline loading, BP changes are similar in high and low endogenous ouabain patients, whereas tubular Na reabsorption increases in the high endogenous ouabain group. Saline loading unmasks differences in renal Na handling in patients with mutant adducin or high endogenous ouabain and exposes an interaction of endogenous ouabain and Trp alleles on BP.

Association of atrial natriuretic peptide and type a natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension.

OBJECTIVES: The goal of our study was to investigate the relationships between atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type A natriuretic peptide receptor (NPRA) gene polymorphisms and left ventricular structure in human essential hypertension. BACKGROUND: Experimental evidence supports a key role for natriuretic peptides in the modulation of cardiac mass. This relationship has not yet been described in human disease. METHODS: A total of 203 hypertensive patients were studied by mono-bidimensional echocardiography. Three markers of the ANP gene (-C664G, G1837A, and T2238C polymorphisms) and a microsatellite marker of both NPRA and BNP genes were characterized. RESULTS: Patients carrying the ANP gene promoter allelic variant had increased left ventricular mass index (117.4 +/- 1.7 g vs. 95.7 +/- 1.7 g, p = 0.005), left ventricular posterior wall thickness (1.14 +/- 0.07 cm vs. 0.96 +/- 0.01 cm, p < 0.0001), left ventricular septal thickness (1.12 +/- 0.10 cm vs. 1.04 +/- 0.01 cm, p = 0.01), and relative wall thickening (47.5 +/- 4.1% vs. 39.4 +/- 5.3%, p = 0.001) as compared with the wild-type genotype. These associations were independent from anthropometric factors and major clinical features and were confirmed in a large subgroup of never-treated hypertensive patients (n = 148). Carrier status of the ANP gene promoter allelic variant was associated with significantly lower plasma proANP levels: 1,395 +/- 104 fmol/ml versus 3,110 +/- 141 fmol/ml in hypertensive patients carrying the wild-type genotype (p < 0.05). A significant association for NPRA gene variants with left ventricular mass index and left ventricular septal thickness was found. The analysis of BNP did not reveal any effect on cardiac phenotypes. CONCLUSIONS: Our findings show that the ANP/NPRA system significantly contributes to ventricular remodeling in human essential hypertension.

Haplotype analysis of carnitine transporters and left ventricular mass in human essential hypertension.

OBJECTIVE: The carnitine-associated alteration of myocardial fatty acid metabolism may be one of the molecular mechanisms underlying left ventricular hypertrophy (LVH) in essential hypertension. We tested the hypothesis that polymorphisms of the genes involved in carnitine transport, OCTN2, CPT1A, CPT1B, and CPT2, might be associated with LVH. DESIGN: Haplotype-based association analysis in an observational study. SETTING: Outpatients from the Nephrology Division of the University Hospital. PATIENTS: A total of 215 never-treated, middle-aged patients with mild essential hypertension. METHODS: Relationships between left ventricular mass index (LVMI) (measured with m-mode echocardiography) and haplotype combinations for 13 common genetic variants selected from single nucleotide polymorphism database (dbSNPs). RESULTS: The SNPs were selected to cover the genomic region of the four loci, and a total of 23 haplotypes were identified: 8 for OCTN2 (H1 to H8), 8 for CPT1A (H9 to H16), 3 for CPT1B (H17 to H19), and 4 for CPT2 (H20 to H23). In a multilocus haplotype analysis, after adjusting for sex, age, systolic blood pressure, diastolic blood pressure, body mass index, and duration of hypertension, a significant effect on LVMI was seen for H13 (+8.9, P = .05), H14 (-5.63, P = .05), H15 (-18.79, P = .0006), H18 (-1.66, P = .03), and H22 (-3.42, P = .004). These significant haplotypes were respectively 3.7%, 1.6%, 1.6%, 39.3%, and 29.7% of the total population. CONCLUSIONS: These results identify the carnitine-transporter gene family as candidate modifiers of LVMI in human hypertension. The use of common SNPs to define informative haplotypes associated with the phenotype of interest is the starting point for progress toward identification of the trapped contributing SNP(s).

Association between aldosterone synthase (CYP11B2) polymorphism and left ventricular mass in human essential hypertension.

OBJECTIVES: The aim of our study was to evaluate the relationship between aldosterone synthase gene polymorphism and cardiac dimensions in essential hypertension. BACKGROUND: Higher aldosterone synthase messenger ribonucleic acid levels in the human heart are accompanied by increased intracardiac aldosterone production, a phenomenon that is associated with cardiac fibrosis and hypertrophy. Recent evidence suggests that a polymorphism (-344C/T) in the promoter region of the aldosterone synthase gene is associated with increased constitutive aldosterone production. METHOD: Relationships between M-mode echocardiographic cardiac dimensions and aldosterone synthase -344C/T polymorphism were studied in 210 never-treated, middle-aged patients (age 41.6 +/- 1.4 years) affected by mild to moderate essential hypertension. Among these patients, 48 had the genotype -C344C, 97 had -C344T, and 65 had -T344T. Patients in the three groups were similar in terms of age, gender, body mass index, and blood pressure. RESULTS: Left ventricular (LV) mass and thickness were positively correlated with the number of T alleles: LV mass (CC, CT, and TT, respectively: 168 +/- 6.9, 179 +/- 5.2, and 193 +/- 6.9 g; p = 0.03), LV septal thickness (0.99 +/- 0.02, 1.03 +/- 0.02, and 11.08 +/- 0.03 cm, p = 0.04), PWT (0.93 +/- 0.03, 0.95 +/- 0.01, and 1.03 +/- 0.02 cm; p = 0.002), and relative wall thickness (38.3 +/- 1.2%, 38.8 +/- 0.8%, and 42.8 +/- 1.1%; p = 0.004). This trend was confirmed by linear regression, suggesting a "major gene" behavior for the T allele. Multiple regression analysis showed that this effect was independent of anthropometric and clinical factors, including adrenal aldosterone. CONCLUSIONS: Our data suggest that -344C/T polymorphism affects LV mass and thickness in essential hypertension, independent of adrenal aldosterone. A role for intracardiac aldosterone synthesis is hypothesized.

ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy.

Renin-angiotensin system reactivity and the constitutive capacity of the renal tubule to reabsorb sodium play a role in the individual response to diuretic therapy; therefore we evaluated the blood pressure (BP) response to hydrochlorothiazide in 87 never-treated individuals with mild essential hypertension, according to ACE gene I/D and alpha-adducin Gly460Trp polymorphism. These genotypes where chosen because previous data showed their interaction in determining the BP response to salt probably was the result of their involvement in the activation of the renin-angiotensin system (ACE) and in the constitutive capacity of the kidney to reabsorb sodium (alpha-adducin) (treatment for 2 months). BP was measured after 3 run-in visits and after the first and second months of treatment by means of a standardized procedure. Data were analyzed by ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for gender, age, and body mass index). Although basal mean BP (MBP) was similar in the different ACE and alpha-adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of alpha-adducin had the largest MBP decrease with treatment (12.7+/-1.9 mm Hg), the effect of the combination of genotypes being additive but not epistatic. These patients had an odds ratio of 15.75 of being a responder to hydrochlorothiazide compared with patients with Gly460Gly+DD, with the least MBP decrease (3.4+/-1.7 mm Hg). Alpha-adducin and ACE I/D polymorphism may be useful to predict the interindividual degree of response to hydrochlorothiazide; the analysis of the combination of the 2 genotypes increases the accuracy of the prediction of response to the drug.