The Functional c.-2G>C Variant of the Mineralocorticoid Receptor Modulates Blood Pressure, Renin, and Aldosterone Levels

Abstract

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.-2GϾC (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.-2GϾC 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. (Hypertension. 2010;56:995-1002.)Key Words: mineralocorticoid Ⅲ aldosterone Ⅲ hypertension Ⅲ nuclear receptor Ⅲ sodium balance T he mineralocorticoid receptor (MR) mediates aldosterone effects on electrolyte balance and blood pressure (BP). Classical MR-expressing tissues include the distal parts of the nephron, colon, salivary glands, and sweat glands, where MR regulates transepithelial sodium transport. However, MRs are also expressed in nonepithelial tissues, including the cardiovascular system and the central nervous system; in these tissues, glucocorticoids represent the predominant endogenous ligand. 1 The MR belongs to the nuclear receptor superfamily and acts as a ligand-activated transcription factor regulating expression of a coordinate set of genes ultimately eliciting physiological aldosterone and cortisol responses. The gene coding for the human MR, NR3C2, is composed of 10 exons and spans over Ϸ400 kb. By means of alternative promoter use, alternative splicing, use of different translational start sites, and genetic polymorphisms, considerable variability in MR function has been observed. 2,3 Sodium handling is highly variable between individuals, and genetic factors are involved in the development of hypertension. 4 Rare mutations of the MR are responsible for mendelian disorders of renal salt handling associated with high or low BP. Loss of function mutations of the MR lead to

Target-based biomarker selection – Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression

“…Furthermore, a common polymorphism of the MR has been linked to stress induced cardiovascular and HPA-axis reactivity (Derijk et al, 2006). A common MR-polymorphism, which leads to less MR-protein expression, is related to higher aldosterone concentrations, similar to our findings, but also to a higher systolic blood pressure (van Leeuwen et al, 2010). Besides genetic influences epigenetic factors have to be taken into account.…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes

“…The other functional SNP is the rs2070951 (C/G), located at two nucleotides from the translation initiation site. The G-allele results in higher activity of the reninangiotensin-aldosterone system and a higher blood pressure, which would be related to the lower MR activity measured for this variant (van Leeuwen et al 2010).…”

The Multifaceted Mineralocorticoid Receptor

“…The relatively common MR-l180V polymorphism has lower transactivation capacity and has not been associated with blood pressure changes. Subjects with the MR-l180V polymorphism have mildly altered the HPA axis, normal levels of cortisol upon awakening, and significant mild stress-induced learning deficits and risk for depression (40, 100, 246, 455). The MR c.-2G > C has a substitution of guanine for cytosine two nucleotides before the start codon, decreasing in vitro translational efficiency.…”