Genes involved in vasoconstriction and vasodilation system affect salt-sensitive hypertension

Lorena Citterio, Marco Simonini, Laura Zagato, Erika Salvi, Simona Delli Carpini, Chiara Lanzani, Elisabetta Messaggio, Nunzia Casamassima, Francesca Frau, Francesca D'Avila, Daniele Cusi, Cristina Barlassina, Paolo Manunta, Lorena Citterio, Marco Simonini, Laura Zagato, Erika Salvi, Simona Delli Carpini, Chiara Lanzani, Elisabetta Messaggio, Nunzia Casamassima, Francesca Frau, Francesca D'Avila, Daniele Cusi, Cristina Barlassina, Paolo Manunta

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Multidimensional scaling plot of stage…
Figure 1. Multidimensional scaling plot of stage 1 cohort.
Individuals in red circle were identified as outliers and subsequently excluded. The two principal components are plotted on the axis.
Figure 2. Renal pressure-natriuresis relationship during acute…
Figure 2. Renal pressure-natriuresis relationship during acute salt load according to the rs3790261 (SLC24A3), rs11893826 (SLC8A1) genotypes.
Urinary sodium excretion (UNa+) as a function of SBP, at basal level (t 0) and after salt load (t 120). The pressure-natriuresis curve is drawn in the left panel considering SLC8A1, rs11893826 polymorphism (carriers of the non risk allele G, green slope, and carriers of the risk allele A, orange slope), in the genetic background of the non risk SLC24A3 AA genotype at rs3790261. It is drawn in the right panel considering the same genotypes for SLC8A1, but within the genetic context of the risk SLC24A3 G allele at rs3790261. The significantly less steep slope of the orange line in the right panel, compared to the three other slopes indicates the need for BP increase in order to excrete the salt load in carriers of that specific allele combination.

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