Gender-specific genetic determinants of hypertension and end organ disease

描述(由申请人提供)：多基因(基本)高血压是心脏病、中风和肾功能衰竭的主要危险因素。尽管人们越来越努力地破译高血压的病因，但高血压及其靶器官并发症的易感性的遗传决定因素仍未完全阐明。我们最近进行了一项比较全基因组扫描，以寻找盐敏感型高血压及其相关靶器官并发症(高血压、肾脏疾病和心肌肥厚)的QTL(数量性状基因座)，这些QTL来自Dahl大鼠的F2交配雄性和雌性种群。我们发现，在三种表型中检测到的大多数QTL都是性别特有的，支持这样的假设，即不同性别之间存在不同的高血压易感性基因决定因素。此外，我们注意到，我们的F2女性队列代表了盐敏感型高血压的绝经前模型，这一事实提出了一个问题，即相似或不同的基因座是否可能导致绝经后女性对盐敏感高血压的易感性，这一问题尤其相关，因为已知绝经后女性患心血管疾病的风险会增加。因此，拟议的研究旨在：a)通过开发携带跨越所检测到的QTL的特定染色体区域的策略性同源品系，进一步划分包含选定血压QTL的雄性和绝经前雌性大鼠的基因组区域；b)对F2(R X S)杂交雌性大鼠群体进行基因组扫描，以寻找影响血压、肾脏疾病和相对心脏重量的QTL，其中雌性大鼠在绝经后(即14个月龄开始高盐挑战开始)会诱发盐敏感型高血压和靶器官并发症。对绝经前和绝经后的基因组扫描进行比较，将根据女性的绝经状态来评估是相似还是不同的染色体区域构成了BP和靶器官损伤的易感性。 项目简介：高血压是心脏病、中风和肾衰竭的主要危险因素。尽管人们越来越努力地破译高血压易感性的遗传决定因素及其靶器官相关并发症，但高血压的遗传基础仍未完全阐明。我们的研究将有助于阐明男性、绝经前和绝经后女性患高血压和靶器官并发症的遗传因素。这些信息将为在男性和女性中独立研究原发性高血压及其靶器官并发症的机制、干预和预防策略提供重要的实验支持。

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.