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（基本）高血压是心脏病，中风和肾衰竭的主要危险因素。尽管越来越多地破译其病因，但易感性易感性及其靶器官并发症的遗传决定因素仍尚待充分阐明。我们最近对盐敏感高血压的QTL（定量性状基因座）进行了比较的总基因组扫描，及其相关的靶靶性和靶器官并发症（高血压肾脏疾病和心脏肥大）在F2中断的男性和女性种群中得出的。我们发现，在这三种表型中检测到的大多数QTL都是性别特异性的，它支持了以下假设：性别之间有高血压易感性的遗传决定因素。此外，我们注意到，我们的F2女同类群代表了一种盐敏感性高血压的绝经前模型，这提出了一个问题，即在绝经后女性中可能赋予盐敏感的高血压易感性是否相似或不同的基因座，这是众所周知的，因为心血管疾病风险增加了，这是众所周知的，这是众所周知的。 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） - 绝经后诱发盐敏感性高血压和靶器官并发症的互化雌性大鼠种群（即：高盐挑战率在14个月大时开始）。绝经前和绝经后基因组扫描之间的比较将根据BP和靶器官损害的敏感性在女性的绝经状态方面评估是否相似或不同的染色体区域。 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破译了高血压易感性及其靶器官相关并发症的遗传决定因素，但高血压的遗传基础仍尚待充分阐明。我们的研究将有助于阐明男性，前和绝经后女性中对高血压和靶向器官并发症的易感性的遗传因素。该信息将为范式转移到男性和女性的独立研究，干预和预防策略的范式转变，以提供重要的实验支持。