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J Clin Endocrinol Metab. 2017 Nov 1;102(11):4124-4135. doi: 10.1210/jc.2017-00957.

The Association of Estrogen Receptor-β Gene Variation With Salt-Sensitive Blood Pressure.

Author information

Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Division of Endocrinology and Metabolism, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Cell and Molecular Biology Laboratory, Department of Cellular Biology and Pharmacology, Faculty of Medicine and Health Sciences, UCSI University, Cheras 56000, Kuala Lumpur, Malaysia.
Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California 90502.
Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California 90502.
Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California 91101.
Division of Endocrinology, Diabetes and Metabolism and Diabetes and Metabolism Research Center, The Ohio State University, Columbus, Ohio 43210.
Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California, Irvine, California 92868.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California 90089.



Hypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER-β, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle.


To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women.


Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging.


Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (β = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1.


The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.

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