Gender-specific genetic determinants of hypertension and end organ disease

高血压和终末器官疾病的性别特异性遗传决定因素

• 批准号: 7461206
• 负责人: NELSON RUIZ-OPAZO
• 金额: $ 40.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7461206
• 关键词: Affect; Age-Months; Alleles; Blood Pressure; Body Weight; Cardiac; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 20; Chromosomes, Human, Pair 5; Congenic Strain; Data; Development; Disease; Elevation; Essential Hypertension; Etiology; Female; Gender; Genetic; Genetic Determinism; Genome; Genome Scan; Genomics; Hand; Heart; Heart Diseases; Heart Hypertrophy; Hour; Hypertension; Inbred Dahl Rats; Injury; Intervention; Investigation; Kidney Diseases; Kidney Failure; Measures; Menopausal Status; Menopause; Modeling; Organ; Phenotype; Population; Postmenopause; Predisposition; Premenopause; Prevention strategy; Quantitative Trait Loci; Rat Strains; Rattus; Relative (related person); Research; Resistance; Risk Factors; Score; Sodium Chloride; Stress; Stroke; Week; Weight; Woman; base; cardiovascular disorder risk; cohort; comparative; genome-wide analysis; male; salt sensitive; trait

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.

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风险因素。尽管越来越多的努力来破译其病因，遗传因素的易感性高血压及其靶器官并发症仍有待充分阐明。我们最近进行了比较全基因组扫描的QTL（数量性状位点）的基础盐敏感性高血压及其相关的靶器官并发症（高血压性肾病和心脏肥大）的F2-intercross男性和女性群体来自达尔大鼠。我们发现，在三个表型中检测到的大多数QTL是性别特异性的，支持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女性队列代表了盐敏感性高血压的绝经前模型，这一事实提出了类似或不同的基因座是否可能赋予绝经后女性盐敏感性高血压易感性的问题，该问题特别相关，因为已知绝经后女性的心血管疾病风险增加。因此，拟议的研究旨在：a）通过开发携带跨越检测到的QTL的特定染色体区域的战略同源菌株，进一步界定男性和绝经前女性中含有选定血压（BP）QTL的基因组区域，和B）对影响BP的QTL进行基因组扫描，在绝经后诱导盐敏感性高血压和靶器官并发症的F2（R x S）-互交雌性大鼠群体中的肾脏疾病和相对心脏重量（即：在14月龄时开始高盐攻击）。绝经前和绝经后基因组扫描之间的比较将评估是否相似或不同的染色体区域是女性BP和靶器官损伤易感性的基础，这取决于她们的绝经状态。 项目叙述：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来破译高血压及其靶器官相关并发症的易感性的遗传决定因素，高血压的遗传基础仍有待充分阐明。我们的研究将有助于阐明男性、绝经前和绝经后女性高血压和靶器官并发症易感性的遗传因素。这些信息将提供关键的实验支持范式的转变，对男性和女性的机制，干预和预防策略原发性高血压及其靶器官并发症的独立调查。