Functional consequences of RAS polymorphisms

RAS 多态性的功能后果

• 批准号: 8011312
• 负责人: Beverly H Koller
• 金额: $ 22.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011312
• 关键词: Accounting; Address; Alleles; Alu Elements; Angiotensin I; Angiotensin II; Angiotensinogen; Blood Pressure; Bradykinin; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Chronic Disease; Clinical; Comorbidity; Complex; Conflict (Psychology); Consensus; Development; Diabetic Nephropathy; Disease; ES Cell Line; End stage renal failure; Enzyme Gene; Enzymes; Etiology; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Haplotypes; Healthcare; Heart Diseases; Hereditary Disease; Homeostasis; Human; Human Genetics; Hypertension; Individual; Introns; Kidney; Kidney Diseases; Link; Linkage Disequilibrium; Methods; Modification; Mus; Organ; Orthologous Gene; Pathogenesis; Peptides; Peptidyl-Dipeptidase A; Phenotype; Play; Population; Predisposition; Prevalence; Recording of previous events; Regulation; Renal function; Renin-Angiotensin System; Reporting; Risk; Risk Factors; Role; Societies; Sodium; Stroke; System; Systems Development; Testing; Tissues; Variant; cardiovascular disorder risk; cell type; disorder risk; embryonic stem cell; enzyme activity; homologous recombination; human DNA; in vivo; insertion/deletion mutation; mouse model; novel; pressure; public health relevance; social; vector

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) plays a critical role in regulation of arterial pressures and sodium homeostasis. Disturbances in this system contribute to the etiology of hypertension, a major risk factor for cardiovascular and renal disease including diabetic nephropathy. As a well established genetic component contributes to the risk of developing hypertension, it is not surprising that polymorphisms in genes encoding the various components of the RAS have been intensely scrutinized both in genetic studies of blood pressure and in studies of conditions in which elevated blood pressure is believed to contribute to disease pathogenesis. Some of the most extensively studied polymorphism(s) of the RAS system are in the gene encoding angiotensin converting enzyme (ACE). This enzyme not only converts angiotensinogen to the biologically active product of the RAS, angiotensin II, but also degrades bradykinin a peptide with vasodilatory activity. While many genetic studies have reported a positive association between polymorphisms in this gene and risk for hypertension and related disorders, an almost equal number have failed to demonstrate such associations. These conflicting results likely reflect the fact that hypertension is a complex genetic disorder resulting from inheritance of a combination of small genetic variations that individually have modest impact. The contribution of a specific variant to hypertension may be difficult to isolate in human populations with varied genetic backgrounds and unique clinical and environmental histories. To address this limitation, we propose to test the hypothesis that polymorphisms in ACE can impact development of hypertension and related diseases using mouse lines which express various alleles of ACE in the absence of the mouse orthologue. Mice homozygous and heterozygous for diseases associated haplotypes will be evaluated under defined environmental conditions for differences in the activity of the RAS, development of hypertension, and development of secondary disease including kidney disease. PUBLIC HEALTH RELEVANCE: Hypertension is a common, chronic disease, and represents an important risk factor for stroke, heart disease and end stage renal disease. With a prevalence of approximately 27% world wide this disease places an enormous economical, health care and social burden on society. There is general consensus that genetic factors contribute to individual susceptibilities to hypertension, and many candidate genes and polymorphisms have been identified through human genetic studies. However, determination of which of these polymorphism(s) is functional and delineation of the mechanism by which the polymorphisms confer risk for disease has been difficult. In this application, using polymorphisms in the ACE gene as an example, we propose a new method for approaching this problem.

描述（由申请人提供）：肾素-血管紧张素系统（RAS）在动脉压和钠稳态调节中起关键作用。该系统的紊乱导致高血压的病因，高血压是心血管和肾脏疾病包括糖尿病肾病的主要危险因素。由于一个公认的遗传成分有助于发展高血压的风险，这并不奇怪，编码RAS的各种成分的基因的多态性已经在血压的遗传研究和在其中血压升高被认为有助于疾病发病机制的条件的研究中被密切审查。RAS系统的一些最广泛研究的多态性在编码血管紧张素转换酶（ACE）的基因中。这种酶不仅将血管紧张素原转化为RAS的生物活性产物血管紧张素II，而且还降解具有血管舒张活性的肽缓激肽。虽然许多遗传学研究报告了该基因多态性与高血压和相关疾病风险之间的正相关性，但几乎相同数量的研究未能证明这种关联。这些相互矛盾的结果可能反映了这样一个事实，即高血压是一种复杂的遗传性疾病，由遗传的小的遗传变异的组合，单独具有适度的影响。在具有不同遗传背景和独特临床和环境史的人群中，可能难以分离特定变异对高血压的贡献。为了解决这一局限性，我们建议测试的假设，即ACE的多态性可以影响高血压和相关疾病的发展，使用小鼠品系表达各种等位基因的ACE在没有小鼠直系同源物。将在规定的环境条件下评价疾病相关单倍型的纯合和杂合小鼠的RAS活性差异、高血压的发生和继发性疾病（包括肾脏疾病）的发生。 公共卫生相关性：高血压是一种常见的慢性疾病，是中风、心脏病和终末期肾病的重要危险因素。这种疾病在全世界的流行率约为27%，给社会带来了巨大的经济、卫生保健和社会负担。遗传因素与高血压易感性的关系已成为普遍共识，许多候选基因和多态性已通过人类遗传学研究确定。然而，确定这些多态性中的哪一个是功能性的以及描绘多态性赋予疾病风险的机制一直是困难的。在这个应用中，使用ACE基因的多态性作为一个例子，我们提出了一个新的方法来解决这个问题。