The association of estrogen receptor-(beta) gene with salt-sensitive hypertension in women but not men

Abstract

Background:Genetic variations in the estrogen receptor have been associated with cardiovascular disease (CVD); most studies have focused on the estrogen receptor-(alpha) gene and not the (beta) gene (ESR2), which may be of more importance in women as ESR2 is the predominant estrogen receptor expressed in vascular smooth muscle cells. To further understand the role of ESR2 and mechanisms underlying hypertension, we investigated the relationship between single nucleotide polymorphisms (SNPs) of ESR2 and salt sensitivity of blood pressure. Methods:In 365 white hypertensive men and women enrolled in HyperPATH, systolic blood pressure (SBP), mean arterial pressure (MAP) and renal blood flow (RBF) assessed by para-aminohippurate clearance, were measured on both low (10 mM Na/day) and high (200mM Na/day) salt diets. The changes in SBP(deltaSBP), MAP(deltaMAP) and RBF(deltaRBF) were calculated in response to sodium load. Gender-specific multivariate regression analysis was used to test the associations between SNP rs10144225 and blood pressure and RBF changes after accounting for age, body mass index, study site, and sibling relatedness. Results:There was no association observed in men; however in hypertensive women, those who were homozygous for major allele A of rs1014425 as compared to minor allele G carriers had lower deltaSBP (15.95(plus or minus)1.97 vs 24.20(plus or minus)3.50mmHg, p=0.02) and deltaMAP (7.61(plus or minus)0.54 vs 14.21(plus or minus)0.93mmHg, p<0.0001), but greater deltaRBF with borderline significance (28.52(plus or minus)5.91 vs 3.41(plus or minus)11.14cc/min, p=0.05). The associations were more prominent in premenopausal hypertensive women (age<50y) with greater differences observed between rs10144225AA vs G carriers in deltaSBP (10.75(plus or minus)3.7 vs 23.52(plus or minus)5.78mmHg, p=0.02), deltaMAP (7.85(plus or minus)1.2 vs 13.24(plus or minus)2.1mmHg, p=0.05), and deltaRBF (31.17(plus or minus)9.9 vs 6.39(plus or minus)9.9cc/min, p<0.0001). In postmenopausal hypertensive women (age>50y), there was no association between rs10144225 and deltaSBP, deltaMAP, or deltaRBF. Conclusion :There is a sex difference within ESR2 rs10144225, with an association present in white, hypertensive women, particularly in premenopausal women, but not men with Na+ sensitive changes in blood pressure and RBF. These findings suggest a role of ESR2 in the gender-specific development of hypertension, specifically in premenopausal women, possibly via defective modulation of renal perfusion when Na+ intake is changed.