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

Abstract

Context: 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.

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

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1.

Trend analysis of DBP changes (ΔDBP) according to ESR2 rs10144225 genotype (data are from the HyperPATH cohort). Participants with minor allele G homozygotes tended to have the highest diastolic SSBP and was followed by heterozygote allele carriers and major allele A homozygotes (P = 0.04). P values were obtained from trend analyses. Data are presented as mean ± SEM. An A indicates adenine and a G indicates guanine.

Figure 2.

Trend analysis of DBP changes (ΔDBP) according to ESR2 rs10144225 genotype stratified by estrogen state (data from the HyperPATH cohort). The premenopausal females (high estrogen state or estrogen-replete state) with minor allele G homozygotes showed the significant trend toward SSBP in the total cohort (P = 0.003) with low estrogen group or estrogen-deplete state (postmenopausal females and/or males) having a nonsignificant trend (P = 0.82). Data are presented as mean ± SEM. An A indicates adenine and a G indicates guanine. The P values were obtained from trend analyses.