Differential genetic basis for pre-menopausal and post-menopausal salt-sensitive hypertension.
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.
Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Victoria L M
VL
Herrera
Khristine A
KA
Pasion
Ann Marie
AM
Moran
Nelson
N
Ruiz-Opazo
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D003433:Crosses, Genetic; D000075222:Essential Hypertension; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006973:Hypertension / Q000235:genetics*; D008126:Lod Score; D008297:Male; D017698:Postmenopause / Q000235:genetics / Q000502:physiology*; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D020303:Rats, Inbred Dahl; D013686:Telemetry