Gender-specific genetic determinants of hypertension and end organ disease

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DESCRIPTION (provided by applicant): Polygenic (essential) hypertension is a leading risk factor for heart disease, stroke and renal failure. Despite increasing efforts to decipher its etiology, the genetic determinants of susceptibility to hypertension and its target organ complications remain to be fully elucidated. We have recently performed a comparative total genome scan for QTLs (quantitative trait loci) underlying salt-sensitive hypertension and its associated target- organ complications (hypertensive renal disease and cardiac hypertrophy) in F2-intercross male and female populations derived from Dahl rats. We found that most QTLs detected across the three phenotypes were gender-specific supporting the hypothesis that there are distinct genetic determinants of hypertension susceptibility between genders. Furthermore, we note that our F2 female cohort represents a pre-menopausal model of salt-sensitive hypertension, fact that raises the question if similar or different loci might confer salt- sensitive hypertension susceptibility in post-menopausal females, issue that is particularly relevant since cardiovascular disease risk is known to increase in post-menopausal women. Thus, the proposed studies are aimed: a) to delimit further the genomic regions containing selected blood pressure (BP) QTLs in male and pre-menopausal females by the development of strategic congenic strains carrying specific chromosomal regions spanning the detected QTLs and b) to perform a genome scan for QTLs affecting BP, renal disease and relative heart weight in an F2 (R x S)-intercross female rat population in which salt-sensitive hypertension and target organ complications are induced after menopause (i.e.: high salt challenge began at 14 months of age). Comparison between pre-menopausal and post-menopausal genome scans will evaluate if similar or different chromosomal regions underlie BP and target organ damage susceptibility in females depending upon their menopausal status. Project Narrative: Hypertension is a leading risk factor for heart disease, stroke and renal failure. Despite increasing efforts to decipher the genetic determinants of susceptibility to hypertension and its target organ associated complications, the genetic underpinnings of hypertension remain to be fully elucidated. Our research will help to elucidate the genetic factors underlying susceptibility to hypertension and target-organ complications in males, pre- and post-menopausal females. This information will provide critical experimental support for the paradigmatic shift towards the independent investigation in males and females of mechanisms, intervention and prevention strategies for essential hypertension and its target organ complications.