Angiotensinogen Gene Polymorphisms and Hypertension

Abstract

Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. Hypertension affects 50 million Americans with a prevalence rate of 25–30% in the adult Caucasian population. The incidence of hypertension and complications resulting from hypertension are even greater in the African-American population. The renin-angiotensin system plays an important role in the regulation of blood pressure, and previous studies have suggested that the angiotensinogen (AGT) gene locus is linked with human essential hypertension. Previous studies have suggested that a single nucleotide polymorphism that converts methionine to threonine at amino acid 235 is associated with hypertension in Caucasian population. This polymorphism is in linkage disequilibrium with A/G polymorphism at −6 position in the promoter of AGT gene. Reporter constructs containing variant A at −6 have increased promoter activity on transient transfection in human liver cells, suggesting that this variant may have increased transcriptional activity. However, this polymorphism is not associated with hypertension in the African-American and Chinese populations. We have found an A/G polymorphism at −217 of the human AGT gene promoter and have shown that frequency of allele A at −217 is significantly increased in the DNA of African-American hypertensive patients. We have also shown that: (a) reporter constructs containing AG gene promoter with nucleoside A at −217 have increased promoter activity on transient transfection; and (b) the C/EBP family of transcription factors and glucocorticoid receptor (GR) bind preferentially to this region of the promoter when nucleoside A is present at −217. In addition, variant −217A is always present with variants −532T, −793A, and −1074T in the human AGT gene promoter. We have also shown that liver enriched transcription factor HNF-3β binds more strongly when nucleoside T is present at −1074. Previous studies have shown that HNF-3β interacts with GR and plays an important role in liver-specific gene expression. These data suggest that AGT haplotype containing −217A, −532T, − 793A, and −1074T may be involved in increased expression of this gene, and may play a role in human hypertension. It will be important to confirm this observation in future human studies and to understand the role of this haplotype in transcriptional regulation using transgenic animals.Key WordsHuman essential hypertensionmolecular geneticsangiotensinogen genetranscription factorssingle nucleotide polymorphism (SNP)haplotypeC/EBPHNF-3