Different polymorphisms of the mineralocorticoid receptor gene are associated with either glucocorticoid or mineralocorticoid levels in hypertension

Abstract

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.

Fig. 1.

Left panel, MR gene structure and LD plot. Right panel, Global P value of haplotype blocks for risk of high-mode UFC and serum aldosterone levels. NTD, N-terminal domain.

Fig. 2.

Comparison of 24-h UFC and serum aldosterone levels by genotypes of rs11724292 and rs7665528 in hypertensives. The numbers in each bar represent the number of subjects within each genotype group, and the error bars represent the se. P value was for the additive model, and both analyses were adjusted for age, gender, body mass index, study sites, and sibling relatedness.