Angiotensinogen Gene Polymorphism at −217 Affects Basal Promoter Activity and Is Associated with Hypertension in African-Americans

Abstract

Hypertension is a serious health problem in Western society, in particular for the African-American population. Although previous studies have suggested that the angiotensinogen (AGT) gene locus is involved in human essential hypertension, the molecular mechanisms involved in hypertension in African-Americans remain unknown. We show that an A/G polymorphism at ؊217 in the promoter of the AGT gene plays a significant role in hypertension in African-Americans. The frequency of the ؊217A allele was increased significantly in AfricanAmerican hypertensive subjects compared with normotensive controls. We also show that the nucleotide sequence of this region of the AGT gene promoter bound strongly to CAAT/enhancer-binding protein (C/EBP) family transcription factors when nucleoside A was present at ؊217. In addition, we show that reporter constructs containing the human AGT gene promoter with nucleoside A at ؊217 had increased basal transcriptional activity upon transient transfection in HepG2 cells compared with reporter constructs with nucleoside G at ؊217. Finally, we show that interleukin-6 treatment in the presence or absence of overexpressed C/EBP␤ increased the promoter activities of reporter constructs containing nucleoside A at ؊217 compared with reporter constructs containing nucleoside G at ؊217. Because the AGT gene is expressed primarily in liver and adipose tissue, and C/EBP family transcription factors play an important role in gene expression in these tissues, we propose that increased transcriptional activity of the ؊217A allele of the human AGT gene is associated with hypertension in African-Americans.Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure (1-3). It is estimated that hypertension affects 50 million Americans with a prevalence rate of 25-30% in the adult Caucasian population, and the incidence of hypertension is even greater in the African-American population. Hypertension is a polygenic disease, and it has been estimated by segregation analysis and twin studies that ϳ45% of the interindividual differences in blood pressure can be accounted for by genetic differences. However, molecular mechanisms involved in the pathophysiology of human hypertension remain unknown. The renin-angiotensin system plays an important role in the regulation of blood pressure, and the octapeptide angiotensin II is one of the most active vasopressor agents (4, 5). Angiotensin II is obtained from its precursor molecule, angiotensinogen (AGT), 1 which is synthesized primarily in liver and adipose tissue and to a lesser extent in kidney, brain, heart, adrenal gland, and vascular walls (6, 7). AGT is first converted by renin to produce a decapeptide, angiotensin I, which is then converted to angiotensin II by the removal of a C-terminal dipeptide by angiotensin-converting enzyme. In experimental as well as clinical studies, administration of renin-angiotensin inhibitors is effective in reducing blood pressure and ending organ damage (8).Jeunemait...

The effect of genetic variation in angiotensinogen on serum levels and blood pressure: a comparison of Nigerians and US blacks

“…[34][35][36] Studies conducted on chimpanzees showed that when exposed to high salt diets their BP levels increase, which is consistent with adaptation to a low sodium environment. 37 This evidence supports the hypothesis that modern humans inherited from their ancestors a gene that was adaptive in an environment low in sodium.…”

“…27 However, when tests of selection are applied to the entire gene, no evidence of a selective sweep or any other form of selection is present. Furthermore, other sites, like the À217, À20 and À18 have been shown to affect basal transcription rates 34,36 and therefore the À6 position is just one among many that could influence the levels of gene expression.…”

Functional Effect of the p22 phox −930 A/G Polymorphism on p22 phox Expression and NADPH Oxidase Activity in Hypertension

“…23 Inflammatory cytokines upregulate C/EBP expression, 24 and cytokine levels have been reported to be increased in phagocytic cells in hypertensive patients. 25 Alternatively, the G allele may be in linkage disequilibrium with other genetic variants that influence the transcriptional activity.…”

Racial Differences in Blood Pressure Response to Angiotensin-Converting Enzyme Inhibitors in Children: A Meta-Analysis

“…ACE inhibitors are less effective as monotherapy in black adults because of low renin levels and a high degree of salt sensitivity (14). This differential response of the renin angiotensin system in blacks may be due to genetic polymorphisms in the angiotensinogen gene (15,16). In black adults, the intrarenal reninangiotensin system is not suppressed as effectively as in whites in response to high salt intake but shows the same level of activation with low salt intake.…”