Mineralocorticoid Receptor and Aldosterone: Interaction Between NR3C2 Genetic Variants, Sex, and Age in a Mixed Cohort

Abstract

Context: Hypertension, a prevalent cardiovascular risk, often involves dysregulated aldosterone and its interaction with the mineralocorticoid receptor (MR). Experimental designs in animal models and human cohorts have demonstrated a sex and age dependency of aldosterone secretion that expands our pathophysiologic understanding.

Objective: This study explores the genetic variation of NR3C2, which encodes MR, in relation to aldosterone, considering age, sex, and race.

Methods: Incorporating 720 Caucasians and 145 Africans from the HyperPATH cohort, we investigated the impact of rs4835490, a single nucleotide risk allele variant, on aldosterone levels and vasculature.

Results: Notably, a significant association between rs4835490 and plasma aldosterone under liberal salt conditions emerged in individuals of European ancestry (P = .0002). Homozygous carriers of the risk A allele exhibited elevated plasma aldosterone levels (AA = 8.1 ± .9 vs GG = 4.9 ± .5 ng/dL). Additionally, aldosterone activation through posture (P = .025) and urinary excretion (P = .0122) showed notable associations. Moreover, genetic interactions with race, sex, and age were observed. Caucasian females under 50 years displayed higher plasma aldosterone, urine aldosterone, and posture aldosterone with the AA genotype compared to females over 50 years, suggesting a potential connection with menopausal or estrogen influences. Interestingly, such age-dependent interactions were absent in the African cohort.

Conclusion: Our study highlights the significance of the NR3C2 genetic variation and its interplay with age, sex, and race in aldosterone activation. The findings point toward an estrogen-modulating effect on MR activation, particularly in women, underlining the role of aldosterone dysregulation in hypertension development. This insight advances our comprehension of hypertension's complexities and opens avenues for personalized interventions. Clinical Trial Registration Number: NCT03029806 (registered January 24, 2017).

Keywords: NR3C2 gene; age; aldosterone; hypertension; mineralocorticoid receptor; sex.

Figure 1.

Mean of 4 traits related to aldosterone across 3 classes of genotype (AA, AG, GG) for the tag single nucleotide variant of the NR3C2 gene (rs4835490) stratified by sex (female vs male) in the Caucasian cohort. (A) Plasma aldosterone baseline (LIB); (B) posture aldosterone; (C) urine aldosterone (LIB); (D) plasma renin activity. The X-axis represents genotype classes; the Y-axis represents the outcome's value. Black bars represent females and grey bars represent males. Error bars represent the SEM. Abbreviations: LIB, liberal salt diet; RES, restricted salt diet (low salt diet).

Figure 2.

Hormonal associations by genotype of NR3C2 rs4835490 stratified by age (<=50 and >50 years) in a Caucasian female cohort. n = 200 age<=50; n = 114 age > 50. (A) Plasma aldosterone baseline (LIB); (B) posture aldosterone (RES); (C) urine aldosterone (LIB); (D) plasma renin activity. The X-axis represents genotype classes; the Y-axis represents the outcome's value. Bar charts represent age at 2 classes (age <=50, black charts and age > 50, grey charts). Error bars represent the SEM. Abbreviations: LIB, liberal salt diet; RES, restricted salt diet (low salt diet).

Figure 3.

Mean of 4 vasculature traits across 2 groups of age stratified by genotype in Caucasian female. (A) Mean of SBP in LIB across 3 class genotypes; (B) mean of DBP in LIB across 3 class genotypes; (C) mean of SSBP in LIB across 3 class genotypes; (D) mean of pulse pressure in LIB across 3 class genotypes. X-axis: 3 classes genotypes of rs4835490 stratified by age group (age<=50 and age > 50) in the Caucasian female; Y-axis: mean value of each trait. Bar charts represent age at 2 classes (age <=50, black charts and age > 50, grey charts). Error bars represent the SEM. Abbreviations: DBP, diastolic blood pressure; LIB, liberal salt diet; SSB, systolic blood pressure; SSBP, salt-sensitive blood pressure.