title: The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels.
abstract: The mineralocorticoid receptor (MR) is essential in the regulation of volemia and blood pressure. Rare mutations in the MR gene cause type 1 pseudohypoaldosteronism and hypertension. In this study we characterized the common MR polymorphism c.-2G>C (rs2070951) in vitro and tested its influence on parameters related to blood pressure regulation and the renin-angiotensin system. In vitro studies showed that the G allele was associated with decreased MR protein levels and reduced transcriptional activation compared with the C allele. Association studies were performed with several outcome variables in 3 independent cohorts: a mild hypertensive group subjected to a salt-sensitivity test, a healthy normotensive group included in a crossover study to receive both a high and low Na/K diet, and a large cohort (The Netherlands Study of Depression and Anxiety), in which blood pressure was measured. Subjects with the GG genotype had significantly higher plasma renin levels both in the mild hypertensive group and in normal volunteers compared with homozygous C carriers. The GG genotype was also correlated with higher plasma aldosterone levels in healthy subjects. In both the mild hypertensive group and The Netherlands Study of Depression and Anxiety cohort the genotype GG was associated with higher systolic blood pressure in males. In conclusion, the G allele of the common functional genetic polymorphism c.-2G>C in the MR gene associates with increased activation of the renin-angiotensin-aldosterone axis and with increased blood pressure, probably related to decreased MR expression.
authors.affiliation: Division of Medical Pharmacology/Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: van Leeuwen
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Caprio
authors.forename: Carolina
authors.initials: C
authors.lastname: Blaya
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fumeron
authors.forename: Paola
authors.initials: P
authors.lastname: Sartorato
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ronconi
authors.forename: Gilberta
authors.initials: G
authors.lastname: Giacchetti
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.forename: Fabio L
authors.initials: FL
authors.lastname: Fernandes-Rosa
authors.forename: Christophe
authors.initials: C
authors.lastname: Simian
authors.forename: Sévrine
authors.initials: S
authors.lastname: Peyrard
authors.forename: Frans G
authors.initials: FG
authors.lastname: Zitman
authors.forename: Brenda W J H
authors.initials: BW
authors.lastname: Penninx
authors.forename: E Ron
authors.initials: ER
authors.lastname: de Kloet
authors.forename: Michel
authors.initials: M
authors.lastname: Azizi
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Roel H
authors.initials: RH
authors.lastname: Derijk
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood* / Q000235:genetics; D000483:Alleles; D001794:Blood Pressure / Q000235:genetics*; D018592:Cross-Over Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D012083:Renin / Q000097:blood* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D012083:Renin