Transgenic mice with -6A haplotype of the human angiotensinogen gene have increased blood pressure compared with -6G haplotype.
Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at -6, and the -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 with -6G. We have found that the 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, and variants -1670G, -1562G, and -1561G almost always occur with -6G. Therefore, the hAGT gene may be subdivided into either -6A or -6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with -6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with -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 the -6A or -6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for 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 with -6G haplotype. Our studies explain the molecular mechanism involved in association of the -6A allele of the hAGT gene with hypertension.
Department of Pathology, New York Medical College, Valhalla, New York 10595, USA.
Sudhir
S
Jain
Andrej
A
Tillinger
Brahmaraju
B
Mopidevi
Varunkumar G
VG
Pandey
Chetankumar K
CK
Chauhan
Steven N
SN
Fiering
Soren
S
Warming
Ashok
A
Kumar
D000483:Alleles; D000808:Angiotensinogen / Q000097:blood* / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D006239:Haplotypes; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism
D051538:Hepatocyte Nuclear Factor 1-alpha; D011965:Receptors, Glucocorticoid; D000808:Angiotensinogen; D012083:Renin