Genes Involved in Vasoconstriction and Vasodilation System Affect Salt-Sensitive Hypertension

Abstract

The importance of excess salt intake in the pathogenesis of hypertension is widely recognized. Blood pressure is controlled primarily by salt and water balance because of the infinite gain property of the kidney to rapidly eliminate excess fluid and salt. Up to fifty percent of patients with essential hypertension are salt-sensitive, as manifested by a rise in blood pressure with salt loading. We conducted a two-stage genetic analysis in hypertensive patients very accurately phenotyped for their salt-sensitivity. All newly discovered never treated before, essential hypertensives underwent an acute salt load to monitor the simultaneous changes in blood pressure and renal sodium excretion. The first stage consisted in an association analysis of genotyping data derived from genome-wide array on 329 subjects. Principal Component Analysis demonstrated that this population was homogenous. Among the strongest results, we detected a cluster of SNPs located in the first introns of PRKG1 gene (rs7897633, p = 2.34E-05) associated with variation in diastolic blood pressure after acute salt load. We further focused on two genetic loci, SLC24A3 and SLC8A1 (plasma membrane sodium/calcium exchange proteins, NCKX3 and NCX1, respectively) with a functional relationship with the previous gene and associated to variations in systolic blood pressure (the imputed rs3790261, p = 4.55E-06; and rs434082, p = 4.7E-03). In stage 2, we characterized 159 more patients for the SNPs in PRKG1, SLC24A3 and SLC8A1. Combined analysis showed an epistatic interaction of SNPs in SLC24A3 and SLC8A1 on the pressure-natriuresis (p interaction = 1.55E-04, p model = 3.35E-05), supporting their pathophysiological link in cellular calcium homeostasis. In conclusions, these findings point to a clear association between body sodium-blood pressure relations and molecules modulating the contractile state of vascular cells through an increase in cytoplasmic calcium concentration.

Left Ventricular Radial Function Associated With Genetic Variation in the cGMP-Dependent Protein Kinase

“…18 Involvement of the cGMP-PKG signaling pathway in cardiac contractility makes the PRKG1 gene a possible candidate for heart failure. In a genome-wide association study, 4 common genetic variants in PRKG1 were significantly associated with the response of diastolic blood pressure to an acute salt load in 478 untreated patients with hypertension. The G, A, and T alleles were associated with significantly increased diastolic blood pressure (Δ ranged from +1.87 to +2.06 mm Hg) after 120 minutes of salt load, and they might be therefore considered as risk alleles for salt sensitivity.…”

“…The G, A, and T alleles were associated with significantly increased diastolic blood pressure (Δ ranged from +1.87 to +2.06 mm Hg) after 120 minutes of salt load, and they might be therefore considered as risk alleles for salt sensitivity. 4 It was suggested that the above-mentioned risk alleles influence the inhibitory effect on renal sodium reabsorption associated with the PKG-1 signaling pathway. 19 These findings might be indicative of the functional importance of the described genetic variations in PRKG1.…”

“…For genotyping of PRKG1 SNPs (rs1904694, rs7897633, and rs7905063), we used the 5′ nuclease allelic discrimination assays with allele-specific minor groove binding probes (TaqMan SNP Genotyping Assay-Applied Biosystem Inc, Foster City, CA) as described in detail elsewhere. 4 …”

“…Furthermore, in cardiac myocytes, adenoviral expression of PKG-1 attenuated hypertrophy via inhibition of calcineurine-nuclear factor of activated T-cells signaling. 3 A recent genome-wide association study 4 found that the common genetic variants (tag) in human PKG-1 gene (PRKG1) were significantly associated with changes in diastolic blood pressure in response to an acute salt load in 478 never-treated patients with hypertension.…”

P4.2 Coronary Risk in Relation to Genetic Variation in Meox2 and Tcf15 in a Flemish Population

“…After DNA extraction from peripheral blood [11], SNPs were genotyped using the TaqMan® OpenArray™ Genotyping System (Life Technologies, Foster City, CA). All DNA samples were loaded at 50 ng/mL and amplified according to the manufacturer's instructions.…”