Gender-specific genetic determinants of hypertension and end organ disease

描述（由申请人提供）：多基因（原发性）高血压是心脏病、中风和肾衰竭的主要危险因素。尽管越来越多的努力破译其病因，遗传决定因素易感性的高血压及其靶器官并发症仍有待充分阐明。我们最近对来自达尔大鼠的f2杂交雄性和雌性种群的盐敏感性高血压及其相关靶器官并发症（高血压肾病和心脏肥厚）的qtl（数量性状位点）进行了比较全基因组扫描。我们发现，在三种表型中检测到的大多数qtl都是性别特异性的，这支持了性别之间存在不同的高血压易感性遗传决定因素的假设。此外，我们注意到我们的F2女性队列代表了绝经前盐敏感性高血压模型，这一事实提出了一个问题，即是否相似或不同的基因座可能赋予绝经后女性盐敏感性高血压易感性，这一问题尤其相关，因为已知绝经后女性心血管疾病风险增加。因此，拟议的研究旨在：a)通过培养携带跨越检测到的qtl的特定染色体区域的战略性同源菌株，进一步确定雄性和绝经前雌性中含有选定血压（BP） qtl的基因组区域；b)对绝经后引起盐敏感性高血压和靶器官并发症的F2 （R x S）杂交雌性大鼠群体中影响血压、肾脏疾病和相对心脏重量的qtl进行基因组扫描(即：高盐挑战从14个月大开始)。绝经前和绝经后基因组扫描的比较将评估是否相似或不同的染色体区域是BP和靶器官损伤易感性的基础，这取决于女性的绝经状态。

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.