title: 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.
authors.affiliation: Division of Nephrology and Dialysis, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele Hospital, Milan, Italy. citterio.lorena@hsr.it
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.forename: Marco
authors.initials: M
authors.lastname: Simonini
authors.forename: Laura
authors.initials: L
authors.lastname: Zagato
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.forename: Simona
authors.initials: S
authors.lastname: Delli Carpini
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzani
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Messaggio
authors.forename: Nunzia
authors.initials: N
authors.lastname: Casamassima
authors.forename: Francesca
authors.initials: F
authors.lastname: Frau
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Avila
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.forename: Cristina
authors.initials: C
authors.lastname: Barlassina
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
mesh_terms: D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics*; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics*
chemical_list: D017673:Sodium Chloride, Dietary