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Three new polymorphisms in human angiotensinogen gene promoter and their role in blood pressure regulation
Author(s) -
Pandey Varunkumar G,
Jain Sudhir,
Mopidevi Brhamaraju,
Kumar Ashok
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1027.14
Subject(s) - haplotype , gene , allele , biology , microbiology and biotechnology , genetically modified mouse , single nucleotide polymorphism , genetics , transgene , promoter , polymorphism (computer science) , gene expression , genotype
Human AGT gene has an A/G polymorphism at ‐6 and ‐6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 Kb of the promoter with ‐6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared to ‐6G. We have found that hAGT gene has three additional SNPs (A/G at –1670, C/G at ‐1562 and T/G at ‐1561). Variants ‐1670A, ‐1562C, and ‐1561T almost always occur with ‐6A (‐6A haplotype); and variants ‐1670G, ‐1562G, and ‐1561G almost always occur with ‐6G (‐6G haplotype). We show that these polymorphisms affect the binding of HNF‐1á and GR to the promoter and reporter construct containing 1.8 Kb hAGT gene promoter with ‐6A haplotype has four fold increased glucocorticoid induced promoter activity as compared to ‐6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either ‐6A or ‐6G haplotype of the hAGT gene and human renin gene. Our ChIP assay shows that HNF1á and GR have stronger affinity to the chromatin obtained from the liver of transgenic mice containing ‐6A haplotype. Our studies also show that transgenic mice containing ‐6A haplotype have increased plasma AGT level and increased blood pressure as compared to ‐6G haplotype. Our studies explain the molecular mechanism involved in association of ‐6A allele of the hAGT gene with hypertension.