Genetics of Hypertension

高血压的遗传学

• 批准号: 8188803
• 负责人: ASHOK KUMAR
• 金额: $ 40.25万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 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 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188803
• 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. PUBLIC HEALTH RELEVANCE: Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. It is estimated that hypertension affects 50 million Americans with a prevalence rate of 25-30% in the adult Caucasian population. Angiotensinogen gene plays an important role in human hypertension. Variants of angiotensinogen gene have been associated with hypertension in Caucasian subjects. Our studies will help us understand molecular mechanism involved in expression of human angiotensinogen gene by these variants in an in vivo situation using transgenic mice.

描述（由申请人提供）：高血压是心肌梗死、心力衰竭、血管疾病、中风和肾衰竭的严重风险因素。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与高加索人和日本人群中血浆AGT水平升高和血压升高相关。然而，与含有-6G等位基因的转基因小鼠相比，含有1.2Kb的具有hAGT基因的-6A等位基因的启动子的转基因小鼠既不显示增加的转录，也不显示增加的血压。我们发现hAGT基因有三个额外的SNP（-1670处的A/G，-1562处的C/G和-1561处的T/G），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、-1561 T、-1562 C、-1670 A）或-6G单倍型（包含-6G、-1561 G、-15652、-1670 G）。我们的瞬时转染试验表明，在肝和肾细胞中，与具有-6G单倍型的报告子构建体相比，具有-6A单倍型的报告子构建体具有四倍增加的糖皮质激素和五倍增加的IL-6诱导的启动子活性。为了了解糖皮质激素和IL-6对hAGT基因-6A和-6G单倍型的转录以及在体内情况下对血压调节的作用，我们重组了180 Kb长的BAC DNA，（含有116 Kb的5 '侧翼区，所有5个外显子和4个内含子，和54 Kb的hAGT基因的3 ′-UTR），并产生含有hAGT基因的-6A或-6G单倍型和人肾素基因的双转基因小鼠。我们的研究表明：（a）血压和（B）与-6G单倍型相比，在含有-6A单倍型的转基因小鼠中肝和肾中的hAGT mRNA增加。我们现在将使用这些转基因小鼠来了解体内情况下糖皮质激素和IL-6对hAGT基因表达和血压的作用。这些研究将为高血压患者提供新的降压策略。 公共卫生相关性：高血压是心肌梗死、心力衰竭、血管疾病、中风和肾衰竭的严重危险因素。据估计，高血压影响5000万美国人，在成年高加索人群中的患病率为25-30%。血管紧张素原基因在人类高血压中起重要作用。血管紧张素原基因变异与高加索人高血压相关。我们的研究将有助于我们了解这些变异体在转基因小鼠体内表达人血管紧张素原基因的分子机制。