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(Hypertension. 2007;49:631.)
© 2007 American Heart Association, Inc.

Original Articles, Part 2

The –20 and –217 Promoter Variants Dominate Differential Angiotensinogen Haplotype Regulation in Angiotensinogen-Expressing Cells

From the Interdisciplinary Genetics Program (M.E.D., C.D.S.), Medical Scientist Training Program (M.E.D.), Department of Biostatistics (M.B.Z.), Department of Internal Medicine (K.R., C.D.S.), and Molecular Physiology and Biophysics (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.

Correspondence to Curt D. Sigmund, Departments of Internal Medicine and Physiology and Biophysics, 3181B Medical Education and Biomedical Research Facility, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail curt-sigmund{at}uiowa.edu

A number of naturally occurring polymorphisms exist in the human angiotensinogen locus, some of which have been associated with essential hypertension, preeclampsia, and other medical disorders. However, to date there has been no comprehensive determination of the significance of specific haplotypes in relation to the regulation of angiotensinogen expression. We cloned the promoters extending from –1219 to +125 bp from 11 ethnically diverse individuals to acquire a representative cross-section of known haplotype diversity. Eight nonredundant haplotypes were identified, fused to luciferase, and studied for their effect on transcriptional regulation in human astrocyte, proximal tubule, and hepatocyte cell lines endogenously expressing angiotensinogen and in a mouse adipocyte cell line. The studies were carried out under baseline conditions, in the presence of the angiotensinogen enhancer, and in response to hormonal stimulation by dexamethasone, ß-estradiol, or testosterone. A statistical model was then constructed to assess the significance of individual polymorphisms. The polymorphisms with the greatest effect on transcription in these cell lines were located at –20 and –217. There were modest haplotype-specific effects of the angiotensinogen enhancer and no haplotype-specific effects of ß-estradiol, dexamethasone, or testosterone treatment. We conclude the following: (1) the –20 and –217 polymorphisms have the largest influence on angiotensinogen transcription, (2) other polymorphisms have a much smaller impact on angiotensinogen transcription, and (3) the transcriptional influence of the promoter polymorphisms may act cell specifically. Therefore, our data support a hypothesis that polymorphisms in the angiotensinogen promoter may act cell specifically to differentially regulate the level of angiotensinogen transcription in angiotensin-producing tissues.

Key Words: transcription • genetics • renin–angiotensin system • hypertension • transfection

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