Non-Coding Variants of Angiotensinogen Gene and Hypertension

血管紧张素原基因的非编码变异与高血压

• 批准号: 9325162
• 负责人: ASHOK KUMAR
• 金额: $ 37万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325162
• 关键词: Address; Adipose tissue; Alleles; Angiotensin II; Angiotensinogen; Animals; Base Sequence; Binding; Binding Sites; Biological Assay; Blood Pressure; Carbohydrates; Chromatin; CpG dinucleotide; DNA; DNA Methylation; Enhancers; Exons; Family; Fatty acid glycerol esters; Female; Genes; Genome; Haplotypes; Heart failure; Hepatocyte; Human; Hypertension; Indium; Individual; Inflammation; Introns; Kidney; Kidney Failure; Knock-in; Liver; Molecular; Mus; Myocardial Infarction; Nucleotides; Organ; Oxidative Stress; Play; Process; Proteins; Renin; Renin-Angiotensin System; Reporter; Risk Factors; Role; Sodium Chloride; Stroke; Tissues; Transcriptional Regulation; Transfection; Transgenic Animals; Transgenic Mice; Untranslated RNA; Untranslated Regions; Variant; Vascular Diseases; base; blood pressure regulation; chromatin immunoprecipitation; chromosome conformation capture; genome wide association study; high salt diet; inflammatory marker; kidney cell; male; promoter; public health relevance; transcription factor; western diet

 DESCRIPTION (provided by applicant): Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure (BP). Recent genome wise association studies (GWAS) have shown that an A/G SNP (rs2004776) located at +1164 in intron-I of the human angiotensinogen (hAGT) gene is associated with hypertension. The nucleotide sequence of hAGT gene containing +1164A allele has stronger homology with HNF-3 binding site as compared to +1164G. HNF3 family belongs to "pioneer" transcription factors whose binding to promoters and enhancers enables chromatin access for other tissue-specific transcription factors. SNPs in the promoter and intron I of the hAGT gene can be divided in 2 major haplotypes: haplotype-I (containing +1164A) and II (containing +1164G). Nucleotide variants in haplotype-I bind more strongly to transcription factors as compared to haplotype-II and reporter construct containing haplotype-I has increased promoter activity as compared to haplotype-II on transient transfection. Transgenic mice containing either haplotype-I or II of the hAGT gene were generated by knock-in approach at the HPRT locus. Preliminary studies have shown that: (a) CpG dinucleotides in the hAGT promoter of TG mice containing haplotype- I are hypo-methylated and accessible to transcription factors as compared to haplotype-II, (b) male TG mice containing haplotype-I have increased basal and GR induced expression of the hAGT gene in liver, kidney and fat as compared to haplotype-II, (c) chromatin from liver and kidney of transgenic animals containing haplotype-I binds more strongly to HNF3β, C/EBPβ, STAT-3 and GR as compared to haplotype-II, (d) double TG mice containing hREN gene and haplotype-I of the hAGT gene have increased BP as compared to haplotype-II which is further increased by Western diet containing high carbohydrate: high fat: high salt diet. In the present application, th role of SNP at +1164 and other cis-acting DNA elements in intron-I on transcriptional regulation of the hAGT gene will be analyzed by DNA methylation assay, chromosome conformation capture (3C) assay, ChIP assay and transient transfection assay. The effect of Western diet on the expression of the hAGT gene, blood pressure regulation, and end organ damage will be analyzed using male/female double transgenic mice containing hREN gene and either haplotype-I or haplotype-II of the hAGT gene.