title: Lanosterol Synthase Gene Polymorphisms and Changes in Endogenous Ouabain in the Response to Low Sodium Intake.
abstract: Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, lanosterol synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that lanosterol synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (<100 mEq/d, 2 weeks) among patients with mild essential hypertension. During the low salt diet, the declines in both systolic BP (SBP: -8.7±1.7 versus -3.0±1.5; P=0.013) and diastolic BP (DBP: -5.1±0.98 versus -1.4±0.94 mm Hg; P<0.05), and the slope of the long-term pressure-natriuresis relationship affected significantly the presence of the lanosterol synthase rs2254524 A variant (AA: 0.71±0.22, AC 0.09±0.13, and CC 0.04±0.11 mEq/mm Hg/24 h; P=0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzani
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Guido
authors.initials: G
authors.lastname: Gatti
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Messaggio
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Simona
authors.initials: S
authors.lastname: Delli Carpini
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Marco
authors.initials: M
authors.lastname: Simonini
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Nunzia
authors.initials: N
authors.lastname: Casamassima
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Laura
authors.initials: L
authors.lastname: Zagato
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: Elena
authors.initials: E
authors.lastname: Brioni
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.).
authors.forename: John M
authors.initials: JM
authors.lastname: Hamlyn
authors.affiliation: From the Genomics of Renal Disease and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milan, Italy (C.L., G.G., L.C., E.M., S.D.C., M.S., N.C., L.Z., E.B., P.M.); and Department of Physiology, University of Maryland, Baltimore (J.M.H.). manunta.paolo@hsr.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004039:Diet, Sodium-Restricted; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D019751:Intramolecular Transferases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010042:Ouabain / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D012313:RNA / Q000235:genetics*; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D010042:Ouabain; D012313:RNA; D019751:Intramolecular Transferases; C021924:lanosterol synthase
keywords: Na-K ATPase; diet; digitalis-like factors; genetic polymorphisms; hypertension