Genetics of Hypertension

高血压的遗传学

• 批准号: 8392241
• 负责人: ASHOK KUMAR
• 金额: $ 35.65万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392241
• 关键词: 5' Flanking Region; Address; Adult; Affect; Alleles; American; Angiotensinogen; Base Sequence; Binding; Biological Assay; Blood Pressure; CCAAT-Enhancer-Binding Proteins; Caucasians; Caucasoid Race; DNA; Dexamethasone; Essential Hypertension; Exons; Female; Gene Expression; Genes; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Glucocorticoid Receptor; Glucocorticoids; Haplotypes; Heart failure; Hepatic; Hepatic Tissue; Hepatocyte; Human; Hypertension; IL6 gene; Interleukin-6; Introns; Japanese Population; Kidney; Kidney Failure; Liver; Messenger RNA; Molecular; Myocardial Infarction; Plasma; Play; Population; Prevalence; Renin; Renin-Angiotensin System; Reporter; Risk Factors; Role; Stroke; Tissues; Transfection; Transgenic Animals; Transgenic Mice; Untranslated Regions; Variant; Vascular Diseases; base; blood pressure regulation; chromatin immunoprecipitation; familial hypertension; human subject; in vivo; kidney cell; male; promoter; receptor binding; transcription factor

DESCRIPTION (provided by applicant): Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. Angiotensinogen (AGT) gene locus is associated with human essential hypertension and its expression is increased by glucocorticoid and IL-6 treatment. Previous studies have shown that variant -6A of the AGT gene is associated with increased plasma AGT level and increased blood pressure in Caucasian and Japanese population. However, transgenic mice containing 1.2 Kb of the promoter with -6A allele of the hAGT gene neither show increased transcription nor increased blood pressure compared to transgenic mice containing -6G allele. We have found that hAGT gene has three additional SNPs (A/G at -1670, C/G at -1562 and T/G at -1561) and variants -1670A, - 1562C, and -1561T almost always occur with variant -6A. Therefore hAGT gene may be subdivided in either -6A haplotype (containing -6A, -1561T, -1562C, -1670A) or -6G haplotype (containing -6G, -1561G, -15652, -1670G). Our transient transfection assays show that reporter construct with -6A haplotype has four fold increased glucocorticoid and five fold increased IL-6 induced promoter activity as compared to the reporter construct with -6G haplotype in liver and kidney cells. In order to understand the role of glucocorticoids and IL-6 on transcription of -6A and -6G haplotypes of the hAGT gene and on the regulation of blood pressure in an in vivo situation, we have re-combineered 180 Kb long BAC DNA (containing 116 Kb of the 5'-flanking region, all five exons and four introns, and 54 Kb of the 3'-UTR of the hAGT gene) and produced double transgenic mice containing either -6A or - 6G haplotype of the hAGT gene and human renin gene. Our studies suggest that: (a) blood pressure and (b) hAGT mRNA in the liver and kidney is increased in transgenic mice containing -6A haplotype as compared to -6G haplotype. We will now use these transgenic mice to understand the role of glucocorticoids and IL-6 on hAGT gene expression and blood pressure in an in vivo situation. These studies will provide new strategies to reduce blood pressure in hypertensive subjects.

描述（由申请人提供）：高血压是心肌梗塞、心力衰竭、血管疾病、中风和肾衰竭的严重危险因素。血管紧张素原 (AGT) 基因位点与人类原发性高血压相关，糖皮质激素和 IL-6 治疗可增加其表达。先前的研究表明，AGT 基因的变体-6A 与白种人和日本人群血浆 AGT 水平升高和血压升高有关。然而，与含有-6G等位基因的转基因小鼠相比，含有带有hAGT基因-6A等位基因的1.2Kb启动子的转基因小鼠既没有表现出转录增加，也没有表现出血压升高。我们发现hAGT基因具有三个额外的SNP（A/G位于-1670、C/G位于-1562和T/G位于-1561），并且变体-1670A、-1562C和-1561T几乎总是与变体-6A一起出现。因此hAGT基因可以细分为-6A单倍型（包含-6A、-1561T、-1562C、-1670A）或-6G单倍型（包含-6G、-1561G、-15652、-1670G）。我们的瞬时转染测定表明，与肝和肾细胞中具有-6G单倍型的报告构建体相比，具有-6A单倍型的报告构建体的糖皮质激素增加了四倍，IL-6诱导的启动子活性增加了五倍。为了了解糖皮质激素和 IL-6 对 hAGT 基因 -6A 和 -6G 单倍型转录以及体内血压调节的作用，我们重新组合了 180 Kb 长的 BAC DNA（包含116 Kb 的 5'-侧翼区域、所有五个外显子和四个内含子，以及 54 Kb 的 3'-UTR hAGT基因）并产生含有hAGT基因和人肾素基因的-6A或-6G单倍型的双转基因小鼠。我们的研究表明：与-6G 单倍型相比，含有-6A 单倍型的转基因小鼠的(a) 血压和(b) 肝脏和肾脏中的hAGT mRNA 增加。我们现在将使用这些转基因小鼠来了解糖皮质激素和 IL-6 在体内情况下对 hAGT 基因表达和血压的作用。这些研究将为高血压患者降低血压提供新策略。