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

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2024 Mar 4

PMID 38437868

Authors

Mahyar Heydarpour

Wasita W Parksook

Luminita H Pojoga

Gordon H Williams

Jonathan S Williams

Affiliations

Soon will be listed here.

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).

References

Hu D, Dong R, Zhang Y, Yang Y, Chen Z, Tang Y . Age‑related changes in mineralocorticoid receptors in rat hearts. Mol Med Rep. 2020; 22(3):1859-1867. PMC: 7411371. DOI: 10.3892/mmr.2020.11260. View

Yokomatsu M, Ohno J . [Para-aminohippuric acid clearance test: (with special reference to RPF and FF)]. Rinsho Byori. 1982; Suppl 49:52-6. View

Guo Z, Poglitsch M, McWhinney B, Ungerer J, Ahmed A, Gordon R . Aldosterone LC-MS/MS Assay-Specific Threshold Values in Screening and Confirmatory Testing for Primary Aldosteronism. J Clin Endocrinol Metab. 2018; 103(11):3965-3973. DOI: 10.1210/jc.2018-01041. View

Keavney B, McKenzie C, Parish S, Palmer A, Clark S, Youngman L . Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators. Lancet. 2000; 355(9202):434-42. DOI: 10.1016/s0140-6736(00)82009-7. View

Tezuka Y, Ito S . The Time to Reconsider Mineralocorticoid Receptor Blocking Strategy: Arrival of Nonsteroidal Mineralocorticoid Receptor Blockers. Curr Hypertens Rep. 2022; 24(7):215-224. PMC: 9300503. DOI: 10.1007/s11906-022-01177-6. View

Brosnihan K, Hodgin J, Smithies O, Maeda N, Gallagher P . Tissue-specific regulation of ACE/ACE2 and AT1/AT2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor-alpha knock-out mice. Exp Physiol. 2008; 93(5):658-64. PMC: 2442755. DOI: 10.1113/expphysiol.2007.041806. View

Brosnihan K, Li P, Ganten D, Ferrario C . Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS. Am J Physiol. 1998; 273(6):R1908-15. DOI: 10.1152/ajpregu.1997.273.6.R1908. View

Lee I, Kim S, Jang H, Kim M, Lee J, Lee Y . Genetic analyses of the chimeric CYP11B1/CYP11B2 gene in a Korean family with glucocorticoid-remediable aldosteronism. J Korean Med Sci. 2010; 25(9):1379-83. PMC: 2923798. DOI: 10.3346/jkms.2010.25.9.1379. View

Angelini A, Di Febbo C, Rullo A, Di Ilio C, Cuccurullo F, Porreca E . New method for the extraction of DNA from white blood cells for the detection of common genetic variants associated with thrombophilia. Pathophysiol Haemost Thromb. 2003; 32(4):180-3. DOI: 10.1159/000070424. View

10.

Javorsky B, Raff H, Carroll T, Algeciras-Schimnich A, Singh R, Colon-Franco J . New Cutoffs for the Biochemical Diagnosis of Adrenal Insufficiency after ACTH Stimulation using Specific Cortisol Assays. J Endocr Soc. 2021; 5(4):bvab022. PMC: 7975762. DOI: 10.1210/jendso/bvab022. View

11.

Shibata S, Ishizawa K, Uchida S . Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension. Hypertens Res. 2016; 40(3):221-225. DOI: 10.1038/hr.2016.137. View

12.

Ahmed S, Hu R, Leete J, Layton A . Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling. Am J Physiol Heart Circ Physiol. 2019; 316(5):H1113-H1123. PMC: 6580385. DOI: 10.1152/ajpheart.00035.2019. View

13.

Zennaro M, Fernandes-Rosa F . 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations. J Endocrinol. 2017; 234(1):T93-T106. DOI: 10.1530/JOE-17-0089. View

14.

Perroud N, Rutembesa E, Paoloni-Giacobino A, Mutabaruka J, Mutesa L, Stenz L . The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. World J Biol Psychiatry. 2014; 15(4):334-45. DOI: 10.3109/15622975.2013.866693. View

15.

Sun B, Chamarthi B, Williams J, Krug A, Lasky-Su J, Raby B . Different polymorphisms of the mineralocorticoid receptor gene are associated with either glucocorticoid or mineralocorticoid levels in hypertension. J Clin Endocrinol Metab. 2012; 97(9):E1825-9. PMC: 3431565. DOI: 10.1210/jc.2012-1486. View

16.

Larsen L, Rose C, Sparso T, Overgaard J, Torekov S, Grarup N . Genetic analysis of the estrogen-related receptor alpha and studies of association with obesity and type 2 diabetes. Int J Obes (Lond). 2006; 31(2):365-70. DOI: 10.1038/sj.ijo.0803408. View

17.

Gorini S, Kim S, Infante M, Mammi C, La Vignera S, Fabbri A . Role of Aldosterone and Mineralocorticoid Receptor in Cardiovascular Aging. Front Endocrinol (Lausanne). 2019; 10:584. PMC: 6716354. DOI: 10.3389/fendo.2019.00584. View

18.

Qing L, Liu L, Zhou L, Zhang F, Gao C, Hu L . Sex-dependent association of mineralocorticoid receptor gene (NR3C2) DNA methylation and schizophrenia. Psychiatry Res. 2020; 292:113318. DOI: 10.1016/j.psychres.2020.113318. View

19.

Baiardi G, Macova M, Armando I, Ando H, Tyurmin D, Saavedra J . Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regul Pept. 2004; 124(1-3):7-17. DOI: 10.1016/j.regpep.2004.06.021. View

20.

Fischer M, Baessler A, Schunkert H . Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res. 2002; 53(3):672-7. DOI: 10.1016/s0008-6363(01)00479-5. View