The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels.
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.
van Leeuwen
Nienke
N
Division of Medical Pharmacology/Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Caprio
Massimiliano
M
Blaya
Carolina
C
Fumeron
Frédéric
F
Sartorato
Paola
P
Ronconi
Vanessa
V
Giacchetti
Gilberta
G
Mantero
Franco
F
Fernandes-Rosa
Fabio L
FL
Simian
Christophe
C
Peyrard
Sévrine
S
Zitman
Frans G
FG
Penninx
Brenda W J H
BW
de Kloet
E Ron
ER
Azizi
Michel
M
Jeunemaitre
Xavier
X
Derijk
Roel H
RH
Zennaro
Maria-Christina
MC
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
D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D012083:Renin