Differential Genetic Basis for Pre-Menopausal and Post-Menopausal Salt-Sensitive Hypertension

Abstract

Essential hypertension affects 75% of post-menopausal women in the United States causing greater cardiovascular complications compared with age-matched men and pre-menopausal women. Hormone replacement and current anti-hypertensive therapies do not correct this post-menopausal increased risk suggesting a distinct pathogenic framework. We investigated the hypothesis that distinct genetic determinants might underlie susceptibility to salt sensitive hypertension in pre-menopausal and post-menopausal states. To determine whether distinct genetic loci contribute to post-menopausal salt-sensitive hypertension, we performed a genome-wide scan for quantitative trait loci (QTLs) affecting blood pressure (BP) in 16-month old post-menopausal F2 (Dahl S×R)-intercross female rats characterized for blood pressure by radiotelemetry. Given identical environments and high salt challenge, post-menopausal BP levels were significantly higher than observed in pre-menopausal (post-menopausal versus pre-menopausal SBP, P<0.0001) and ovariectomized (post-menopausal versus ovariectomized SBP, P<0.001) F2-intercross female rats. We detected four significant to highly significant BP-QTLs (BP-pm1 on chromosome 13, LOD 3.78; BP-pm2 on chromosome 11, LOD 2.76; BP-pm3 on chromosome 2, LOD 2.61; BP-pm4 on chromosome 4, LOD 2.50) and two suggestive BP-QTLs (BP-pm5 on chromosome 15, LOD 2.37; BP-f1 on chromosome 5, LOD 1.65), four of which (BP-pm2, BP-pm3, BP-pm4, BP-pm5) were unique to this post-menopausal cohort. These data demonstrate distinct polygenic susceptibility underlying post-menopausal salt-sensitive hypertension providing a pathway towards the identification of mechanism-based therapy for post-menopausal hypertension and ensuing target-organ complications.

Worse Renal Disease in Postmenopausal F2[Dahl S x R]-Intercross Rats: Detection of Novel QTLs Affecting Hypertensive Kidney Disease

“…As shown in Figure 1, glomerular injury scores were increased significantly in postmenopausal and premenopausal ovariectomized F2[Dahl S x R]-intercross rats when compared with premenopausal female rats (P<0.01). These results indicate concordance of hypertension and renal disease susceptibility in postmenopausal F2[Dahl S x R]intercross-rats showing increased susceptibility to salt-sensitive hypertension [13] and hypertensive nephrosclerosis in postmenopausal state.…”

“…To determine whether worse hypertension observed in postmenopausal rats [13] is also associated with increased end-organ disease or the opposite as observed in some clinical studies [12], we analyzed established quantitative measures of hypertensive nephrosclerosis, glomerular injury scores (GIS) [16] and compared GIS measures among postmenopausal F2[Dahl S x R]-intercross rats, premenopausal ovariectomized F2[Dahl S x R]-intercross rats [15], and premenopausal F2[Dahl S x R]-intercross rats [14]. As shown in Figure 1, glomerular injury scores were increased significantly in postmenopausal and premenopausal ovariectomized F2[Dahl S x R]-intercross rats when compared with premenopausal female rats (P<0.01).…”

“…Given that some patients have worsening of kidney function with hormone replacement therapy [12], it is important to determine the phenotype of hypertensive kidney disease in a postmenopausal F2[Dahl S x R]-intercross rat cohort which has demonstrated increased salt-sensitive hypertension in postmenopausal rats far greater than the mean blood pressure levels reached in both premenopausal female rats and premenopausal ovariectomized female rats [13], and wherein experimental environmental and genetic confounders are minimized if not eliminated. Furthermore, given that distinct genetic factors, or quantitative trait loci (QTLs), underlie premenopausal hypertension [13], [14] as well as in premenopausal ovariectomized female rats [15], it is important to determine whether distinct QTLs also underlie postmenopausal hypertensive kidney disease.…”

“…Furthermore, given that distinct genetic factors, or quantitative trait loci (QTLs), underlie premenopausal hypertension [13], [14] as well as in premenopausal ovariectomized female rats [15], it is important to determine whether distinct QTLs also underlie postmenopausal hypertensive kidney disease. Identification of distinct QTLs for postmenopausal renal disease will elucidate that premenopausal and postmenopausal kidney disease has distinct pathogenic mechanisms.…”

Report of the National Heart, Lung, and Blood Institute Working Group on Sex Differences Research in Cardiovascular Disease

“…Through genetic mapping studies, it is clear that some cardiovascular trait loci differ between sexes 31 and that these genetic determinants can influence pre- and post-menopausal susceptibility to disease. 32 Future studies that go beyond identification of single nucleotide variants are needed to investigate the role of genetic variants in promoter response elements for hormone receptors. 33 More complex statistical analyses to evaluate the impact of expression changes on molecular networks and alteration of disease phenotype are also warranted.…”