OBJECTIVE: Both aldosterone and cortisol can activate the mineralocorticoid receptor (MR). Polymorphisms in the MR gene have been inconsistently shown to be associated with risk of hypertension and aldosterone and cortisol levels. The purpose of this project was to investigate the association of MR gene variants with serum aldosterone and a previously identified hypertension subgroup with higher urinary free cortisol (UFC) levels (high-mode UFC) in a rigorously phenotyped Caucasian hypertensive cohort. MATERIALS AND METHODS: A haplotype-based tagging single nucleotide polymorphism (htSNP) association study was conducted in the HyperPATH cohort of 570 hypertensive Caucasian subjects on a salt-controlled diet. Haplotypes generated from 74 htSNP representing the common genetic variations of the entire MR gene were analyzed by comparing high- vs. normal-mode UFC groups and the association with serum aldosterone levels. RESULTS: Of the observed 20 haplotype blocks, there were three main linkage disequilibrium (LD) regions with high recombination rates between adjacent regions. Overlaying gene structure on this LD map revealed that block 1-8 corresponded to exon 5-9 [ligand binding domain (LBD)], blocks 9-18 to exon 3-4 [DNA binding domain (DBD)], and block 19-20 to exon 1-2 (N-terminal domain). Haplotype association results showed that DBD-aligned LD blocks were associated with high-mode UFC status (global P values, 0.0004 to 0.05). The LBD-aligned LD blocks showed significant associations with serum aldosterone levels. CONCLUSIONS: These findings imply that there may be differential functional importance of the DBD and LBD of the MR in the regulation of glucocorticoid and aldosterone levels in hypertensive subjects.
OBJECTIVE: Both aldosterone and cortisol can activate the mineralocorticoid receptor (MR). Polymorphisms in the MR gene have been inconsistently shown to be associated with risk of hypertension and aldosterone and cortisol levels. The purpose of this project was to investigate the association of MR gene variants with serum aldosterone and a previously identified hypertension subgroup with higher urinary free cortisol (UFC) levels (high-mode UFC) in a rigorously phenotyped Caucasian hypertensive cohort. MATERIALS AND METHODS: A haplotype-based tagging single nucleotide polymorphism (htSNP) association study was conducted in the HyperPATH cohort of 570 hypertensive Caucasian subjects on a salt-controlled diet. Haplotypes generated from 74 htSNP representing the common genetic variations of the entire MR gene were analyzed by comparing high- vs. normal-mode UFC groups and the association with serum aldosterone levels. RESULTS: Of the observed 20 haplotype blocks, there were three main linkage disequilibrium (LD) regions with high recombination rates between adjacent regions. Overlaying gene structure on this LD map revealed that block 1-8 corresponded to exon 5-9 [ligand binding domain (LBD)], blocks 9-18 to exon 3-4 [DNA binding domain (DBD)], and block 19-20 to exon 1-2 (N-terminal domain). Haplotype association results showed that DBD-aligned LD blocks were associated with high-mode UFC status (global P values, 0.0004 to 0.05). The LBD-aligned LD blocks showed significant associations with serum aldosterone levels. CONCLUSIONS: These findings imply that there may be differential functional importance of the DBD and LBD of the MR in the regulation of glucocorticoid and aldosterone levels in hypertensive subjects.
Authors: Fabio L Fernandes-Rosa; Margaret de Castro; Ana Claudia Latronico; Wolfgang G Sippell; Felix G Riepe; Sonir R Antonini Journal: J Clin Endocrinol Metab Date: 2006-06-06 Impact factor: 5.958
Authors: W R Litchfield; S C Hunt; X Jeunemaitre; N D Fisher; P N Hopkins; R R Williams; P Corvol; G H Williams Journal: Hypertension Date: 1998-02 Impact factor: 10.190
Authors: Roel H DeRijk; Stefan Wüst; Onno C Meijer; Maria-Christina Zennaro; Ilona S Federenko; Dirk H Hellhammer; Gilberta Giacchetti; Erno Vreugdenhil; Frans G Zitman; E Ronald de Kloet Journal: J Clin Endocrinol Metab Date: 2006-10-03 Impact factor: 5.958
Authors: Sekar Kathiresan; Martin G Larson; Emelia J Benjamin; Diane Corey; Joanne M Murabito; Caroline S Fox; Peter W F Wilson; Nader Rifai; James B Meigs; Gesa Ricken; Richard P Lifton; Daniel Levy; Ramachandran S Vasan Journal: Am J Hypertens Date: 2005-05 Impact factor: 2.689
Authors: Felix G Riepe; Johannes Finkeldei; Luisa de Sanctis; Silvia Einaudi; Alberto Testa; Beate Karges; Michael Peter; Matthias Viemann; Joachim Grötzinger; Wolfgang G Sippell; Geza Fejes-Toth; Nils Krone Journal: J Clin Endocrinol Metab Date: 2006-09-05 Impact factor: 5.958
Authors: D S Geller; A Farhi; N Pinkerton; M Fradley; M Moritz; A Spitzer; G Meinke; F T Tsai; P B Sigler; R P Lifton Journal: Science Date: 2000-07-07 Impact factor: 47.728