(Hypertension. 1997;30:1325-1330.)
© 1997 American Heart Association, Inc.
Articles |
Essential Hypertension and 5' Upstream Core Promoter Region of Human Angiotensinogen Gene
From the Second Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan.
Correspondence to Satoshi Umemura, MD, Second Department of Internal Medicine, Yokohama City University University School of Medicine, 3–9, Fukuura, Kanazawa-ku, Yokohama 236, Japan.
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Abstract |
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Abstract The angiotensinogen (AGT) gene M235T variant is associated with essential hypertension and elevated plasma AGT concentrations, although the underlying mechanisms are unknown. Recent studies have suggested that AGCE 1 (human AGT gene core promoter element 1) located in the 5' upstream core promoter region (position -25 to -1) of the human AGT gene has an important part in the expression of AGT mRNA by binding with transcription factor AGCF 1 (human AGT gene core promoter element binding factor 1), and a mutation at -20 from adenine to cytosine (A-20C) increases the level of expression of this transcript. We therefore examined subjects with this mutation to study the association with increased plasma AGT concentrations and with essential hypertension. One hundred eighty-eight subjects receiving no antihypertensive medication were examined with regard to the correlation between A-20C and plasma AGT concentrations, and 234 subjects were studied with respect to the association between A-20C and essential hypertension. A-20C was determined by polymerase chain reaction–restriction fragment length polymorphism analysis with EcoOR 109I. Multiple regression analysis showed a weak but significant correlation between A-20C and plasma AGT concentrations (P=.047) and essential hypertension (P=.049). The results suggest that A-20C may underlie the increase in plasma AGT concentrations and be involved in the development of essential hypertension.
Key Words: hypertension, essential • core promoter • angiotensinogen • mutation
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Introduction |
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The human RAS plays a pivotal role in blood pressure regulation.1 Recent molecular biological studies have indicated that in addition to the classic endocrine system, local RAS systems may also be an important element in the pathogenesis of cardiovascular diseases such as hypertension.2 EH is considered a polygenic heritable trait.3 Although several epidemiological studies have corroborated this hypothesis, genetic studies have not provided definitive evidence that EH is inherited. The AGT gene, the source of the RAS generated mainly in the liver, has been implicated in EH.3 Previous studies have suggested that the human AGT gene variants M235T in exon 24 and GT repeat in the 3' downstream region5 are responsible for EH; however, this remains controversial.6,7 Although elevated plasma AGT concentrations have been associated with EH8 and with M235T variants,4 the molecular mechanisms leading to increased plasma AGT concentration cannot be explained solely on the basis of this mutation alone. The GT repeat in the 3' downstream region of the AGT gene also cannot explain the mechanism of elevated plasma AGT concentrations in EH. These mutations have therefore been postulated to be genetic markers of other causative genes or mutations. The molecular basis for the increase in plasma AGT concentrations in patients with EH remains unclear.
Recent studies of transgenic animals have suggested that transcriptional mechanisms of the AGT gene may be involved in the pathogenesis of hypertension.9–11 Angiotensinogen-deficient mice developed by homologous recombination in mouse embryonic stem cells do not produce AGT and are hypotensive, indicating that AGT has a vital role in the maintenance of blood pressure and the development of hypertension.12,13 In vivo transfection experiments using decoy oligodeoxynucleotides against the transcriptional cis-element of the AGT gene have demonstrated a transient decrease in blood pressure in SHR, accompanied by reductions in plasma AGT and angiotensin II levels. These studies suggested that the transcriptional cis-element of the AGT gene may regulate blood pressure by controlling circulating levels of AGT.14 In addition, Yanai et al reported that the 5' upstream core promoter region of the human AGT gene is essential for the transcription of AGT mRNA15 and that the ubiquitously expressed nuclear factor AGCF 1 binds to AGCE 1 (position -25 to -1 of the AGT gene) located between the TATA box and the transcription initiation site.15 Furthermore, an adenine-to-cytosine transition at nucleotide -20 of the 5' upstream core promoter region of the human AGT gene (A-20C) has been demonstrated,4 and recent transient transfection data indicate that an AGT promoter containing the A-20C mutation transcribes a reporter gene at a greater level than the wild type (A-20A).16 Therefore, the A-20C mutation may also affect the transcription activity of AGT mRNA in humans and thereby alter the plasma AGT level.
To further investigate the genetic basis for EH, we studied the association of the A-20C mutation with plasma AGT levels and the development of EH in humans. Multiple regression analysis suggested a weak but significant contribution of this mutation to plasma AGT levels in normal subjects and in patients with EH.
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Methods |
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Subjects
First, we studied the relation between plasma AGT concentration and the A-20C mutation in 188 subjects recruited randomly from our outpatient clinic. No subject had previously received antihypertensive drugs. Blood samples were collected for isolation of genomic DNA and plasma. The PCR-RFLP method was used to determine A-20C mutations; plasma AGT concentrations were also measured. The correlations among plasma AGT concentrations, age, BMI, SBP, DBP, and lipids (such as total cholesterol concentration, triglyceride concentration, and HDL-cholesterol concentration) were examined in these subjects. Multivariate linear regression analysis was performed to study relations between plasma AGT concentration and A-20C, age, BMI, sex, total cholesterol concentration, triglyceride concentration, and DBP.
Second, we investigated the relations between the A-20C mutation and the development of EH by examining genomic DNA randomly selected from patients admitted to Yokohama City University Hospital. A total of 234 adult Japanese subjects were studied. Informed consent was obtained from all subjects before enrollment. The PCR-RFLP method was used to determine A-20C mutations. Multivariate logistic regression analysis was used for statistical analysis.
Diagnosis of EH
EH was diagnosed on the basis of a SBP of more than 140
mm Hg, a DBP of more than 90 mm Hg, or both. Secondary
hypertension was excluded by clinical history; physical examination;
laboratory tests, and biochemical and hormonal evaluations (including
serum creatinine, blood urea nitrogen, electrolytes,
glucose, and liver function) and renoscintigraphy if
necessary. Since our department specializes in
cardiovascular disease, the frequency of EH in the
second study was higher than that of the general population.
Genomic DNA Extraction
Genomic DNA was extracted as described
previously.17,18 Ten milliliters of blood was collected
into heparinized tubes, and white blood cells were separated. Genomic
DNA was conventionally extracted from the peripheral blood
leukocytes by proteinase K digestion of nuclei. Phenol extraction was
followed by ethanol precipitation of the DNA.
PCR-RFLP Method
To determine the A
C transition at nucleotide -20
of the 5' upstream region of the core promoter of the AGT gene, we
constructed 3' and 5' primers as follows: 5' primer, 5'-AGA GGT CCC AGC
GTG AGT GTC-3' (from -166 to -144); 3' primer, 5'-AGC CCA CAG CTC AGT
TAC ATC-3' (from 81 to 101). PCR was performed in a final volume of 30
µL containing 200 ng DNA, 10 pmol of each primer, 250 mmol/L of
each of the four dNTPs, 1.5 mmol/L MgCl2, 50
mmol/L KCl, 10 mmol/L Tris HCl at pH 8.4, and 2 U of
Taq polymerase (TAKARA). The PCR conditions were as follows:
30 cycles at 94°C for 30 seconds, 64°C for 1 minute, and 72°C for
1 minute. After PCR, 265-bp products including the 5' upstream core
promoter region were obtained. Then, 3 µL of unpurified product
was diluted to 20 µL in the recommended restriction buffer containing
2 U of EcoOR 109I (TAKARA) and digested for at least 2 hours
at 37°C. These samples were applied to 8% polyacrylamide gel
and subjected to electrophoresis at 150 mA for 3 hours. The DNA was
visualized directly by ethidium bromide staining (Fig 1
). The M235T variant of the
AGT gene at exon 2 was determined as described
previously.17
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Measurement of Plasma AGT Concentration
Plasma AGT concentrations were measured as described
previously.19,20 Blood samples for measurement of plasma
AGT concentration were withdrawn with EDTA as anticoagulant and
centrifuged immediately. The plasma was separated and frozen at
-80°C until assay. For measurement of plasma AGT concentration,
100-µL aliquots of plasma were incubated with 5 µL
8-hydroxyquinoline, 5 µL dimercaprol, 25 µL Na2EDTA, 50
µL human kidney renin, and 65 µL Tris-acetate buffer (pH 8.0)
containing lysozyme for 12 hours at 37°C, and the generated
angiotensin I was measured by radioimmunoassay (RENIN
RIABEAD Ang I kit, Dainabot Ltd).
Statistical Analysis
Allele frequencies were estimated by the gene-counting
method. Continuous variables are expressed as mean±SE according to
clinical features. For the regression model, the genotype
effect was assumed to be additive (with scores of 0, 1, and 2 assigned
for genotype AA, AC, and CC in AC transition at -20 of 5'
upstream of core promoter region of the AGT gene, respectively),
dominant (with scores of 0 for AA and 1 for AC and CC combined), or
recessive (with scores of 0 for CC and AC combined and 1 for
CC).21 In the M235T variant of the AGT gene in
exon 2, the genotype effect was assumed to be additive (with
scores of 0, 1, and 2 assigned for genotype MM, TM, and TT,
respectively). Analysis of differences in means or proportions
between genotypes was conducted with the use of the inheritance
models outlined above. To evaluate EH, dichotomous criteria for EH (ie,
subjects with EH=1, subjects without EH=0) were adopted. Age was sorted
into three groups as follows: with scores of 0, 1, and 2 assigned for
age <60, 
60 to <70, and 70, respectively, in the second study.
Unpaired t tests were used to analyze differences in
general characteristics between the control and hypertensive groups in
the second study. Statistical analyses were performed with
SPSS, version 6.1, on a Macintosh computer. P<.05 was
considered to indicate statistical significance.
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Results |
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Fig 1
shows typical results of polyacrylamide gel
electrophoresis in which the PCR products were amplified from human
genomic DNA and digested with EcoOR 109I. The allele
with -20A that lacked the enzyme-restriction site was designated A
(wild type: 205 bp). On the other hand, the allele that had the
enzyme-restriction site in the presence of cytosine transition
at nucleotide position -20 was designated as C (mutant
type: 137 bp). Thus, there were three possible genotypes: AA,
AC, and CC.
Relation Between AGT Genotype and Plasma AGT
Concentration
The general characteristics of the subjects in the first study and
their genotype and allele frequencies of A-20C are
summarized in Tables 1 and 2, respectively. The subjects comprised
81 men and 107 women. Univariate regression
analysis revealed positive correlations between plasma AGT
concentration and SBP (r=.232, P=.0015) and AGT
concentration and DBP (r=.183, P=.0126),
and between BMI and SBP (r=.282, P=.0001) and BMI
and DBP (r=.284, P=.0001) (Table 3). After adjusting for these factors by
multivariate linear regression analysis, plasma
AGT concentration significantly correlated with A-20C
(P=.0472) and total cholesterol concentrations
(P=.0029) but not with age, BMI, sex,
triglyceride concentration, or DBP (P=.1398,
P=.1535, P=.3987, P=.4644, and
P=.1345, respectively) (Table 4). Fig 2
graphically depicts the plasma AGT concentration according to each
genotype. The plasma AGT concentration linearly increased
according to genotype (ie, AA<AC<CC), although ANOVA showed
no differences in plasma AGT concentration among the three
genotypes (P=.2981).
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Relation Between AGT Genotype and EH
The general characteristics of the subjects in the second study
and their genotype and allele frequencies are summarized in
Tables 5 and 6, respectively. The hypertensive group
had a greater BMI than did the normotensive group (P=.0142)
(Table 5). 
2 analysis showed no difference in
the distribution of genotype or allele frequency between
the EH and normotensive subjects (2=5.339,
2=1.407 and P=.069, P=.235,
respectively). However, multivariate logistic
regression analysis indicated that age, BMI, and A-20C mutation
status significantly contributed to EH in an additive manner
(P=.0104, P=.0471, and P=.0489;
r=.1516, r=.0988, and r=.0971,
respectively) (Table 7). However, in
other inheritance models, we found no significant contribution of this
genotype to human EH (P=.9443 in recessive
inheritance model; P=.1222 in dominant inheritance
model).
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Discussion |
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EH is a heritable polygenic trait. Recently, numerous studies using molecular biological methods have attempted to identify candidate genes responsible for EH.18,22 Previous studies have implicated the AGT gene in the pathogenesis of EH.4,5 Although M235T variant in exon 2 (M235T) and GT dinucleotide repeats in the 3' downstream untranslated region (GT repeat) of the human AGT gene have been linked to EH, this point remains controversial.6,7 The results of previous studies suggest that these mutations are either causative mutations or genetic markers for other candidate genes and mutations. Given the significant positive correlation between plasma AGT concentration and blood pressure,8 as reconfirmed in our study (Table 3
), elevated AGT concentrations may result in increased
blood pressure. Elevated plasma AGT concentrations are assumed to at
least partly reflect increased AGT mRNA levels in the
liver.19 Since the essential transcriptional
cis-element of the AGT gene lies in the 5'
upstream core promoter region,14,15 M235T and GT repeats of
the AGT gene would have little influence on its
transcription. Therefore, these variants are most likely genetic
markers for other causative genes or mutations. Recently, Yanai et al demonstrated that a ubiquitously expressed nuclear factor, AGCF 1, bound to a cis-acting DNA element, AGCE 1, positioned from -25 to -1 located between the TATA box and the transcription initiation site of the AGT gene.15 Furthermore, they showed that a substitutional mutation in this region that disrupted the AGCF 1 binding site had a greater effect on promoter activity than did a nonsense mutation in the TATA sequence, suggesting that AGCE 1 as well as the TATA box plays a key role in mediating expression of the human AGT gene. Similarly, in studies using Hep G2 cells (human hepatoma cells) Zhao et al16 also found that adenine-to-cytosine substitution at nucleotide -20 of the human AGT gene increased its transcription activity. Therefore, we hypothesized that increased transcription activity of the AGT gene in subjects with this A-20C mutation may elevate plasma AGT levels, thus leading to a rise in blood pressure. In the present study, a multivariate linear regression model with additive inheritance score of genotype showed that the AGT concentration linearly increased according to genotype (ie, AA<AC<CC), suggesting that A-20C mutations contribute to the development of EH. BMI and age were also contributing factors to EH in our study, confirming prior results. We previously reported that hepatic AGT mRNA levels, measured in liver biopsy specimens, positively correlated with plasma AGT levels in subjects with chronic hepatitis.19 Furthermore, numerous other factors are thought to be involved in the regulation of plasma AGT levels. Tissue AGT, which is synthesized in several tissues besides the liver, such as the brain, heart, aortae, adrenals, kidneys, and fat, may also play a part in the regulation of plasma AGT.23–26 Recently, we reported that the expression of tissue AGT is regulated differently in SHR and Wistar-Kyoto rats and showed that the development of hypertension is accompanied, at least temporally, by increases in plasma AGT concentration as well as cardiac and adipogenic AGT mRNA in SHR.27 In addition, hormonal factors such as thyroid hormones also stimulate plasma AGT levels.28,29 Thyroid hormones are thought to regulate hepatic AGT synthesis at the transcription level.30,31 Other factors such as angiotensin II,32,33 bilateral nephrectomy (circulating renin),34 and 17ß-estradiol35 also regulate plasma AGT levels. Thus, altered transcription and metabolism in various tissues may be determinants of plasma AGT concentration. A recent study by Inoue et al36 demonstrated that a point mutation at -6 of the 5' upstream cis-element of the human AGT gene was associated with increased transcription activity of AGT mRNA, suggesting that the A-20C mutation is a genetic marker and that an unrelated mechanism, such as altered AGT metabolism or clearance, is responsible for elevated plasma AGT levels. Whereas the circulating endocrine RAS appears responsible for acute cardiovascular effects, the tissue RAS may participate in chronic processes such as secondary structural changes and thereby contribute substantially to the pathogenesis of hypertension and other cardiovascular disorders, including cardiac hypertrophy and coronary artery disease.37 Although in this study we did not examine AGT production and metabolism in local tissues such as vascular wall, we measured plasma angiotensin I concentrations by radioimmunoassay and found no significant differences among the three genotypes (AA=0.69±0.06 ng/mL, AC=0.60±0.04 ng/mL, and CC=0.59±0.08 ng/mL, P=.4595), suggesting the possible involvement of AGT gene polymorphism in local AGT production.
EH is a multigenic and multifactorial disease, and it is doubtful
that a single nucleotide change of the AGT gene
is solely responsible for the onset of this disorder; although the
A-20C mutations could have a slight aggravating effect. We demonstrated
a weak but significant contribution of A-20C to EH using
multivariate logistic regression models. In contrast,
we found no significant association when 2
analysis was performed with 2x3 contingency tables.
Association studies using 2 analysis are useful
in examining the association between genotype and
phenotype. However, association studies are liable to
bias38,39 because they require case-control
analysis. We therefore used multiple logistic regression
analysis to study multiple risk factor diseases,40
and the subjects were randomly selected to minimize the risk of
bias.
We also found a significant correlation between plasma AGT concentrations and total cholesterol levels in this study, although the study did not permit identification of the underlying cause. Positive relations between serum cholesterol level and blood pressure have been found in many epidemiological studies.41 In addition, Goodfriend et al reported that high aldosterone levels may be a link between dyslipidemia and hypertension.42 There is increasing recognition that high blood pressure is only one facet of a metabolic syndrome that represents a cluster of risk factors for the long-term development of cardiovascular disease.43 Thus, plasma AGT and total cholesterol concentrations may be linked by factors such as blood pressure or other metabolic mechanisms, although verification of this hypothesis must await further investigation.
In conclusion, we found a significant contribution of AC transition
in the 5' upstream core promoter region of the human AGT
gene to plasma AGT concentration and to EH. Our results suggest that
this mutation increases transcription activity of AGT mRNA and may
thereby contribute to the development of EH in humans.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants from the Ministry of Education, Science, and Culture of Japan (Nos. 08258222, 08407020, 02670404, 05670956, 09770492) and by a grant from the Uehara Memorial Foundation.
Received March 16, 1997; first decision April 15, 1997; accepted July 3, 1997.
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 M. Sugimoto, T. Furuta, N. Shirai, C. Kodaira, M. Nishino, M. Ikuma, H. Sugimura, and A. Hishida Role of angiotensinogen gene polymorphism on Helicobacter pylori infection-related gastric cancer risk in Japanese Carcinogenesis, September 1, 2007; 28(9): 2036 - 2040. [Abstract] [Full Text] [PDF]
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A. A. Sethi, B. G. Nordestgaard, M.-L. M. Gronholdt, R. Steffensen, G. Jensen, and A. Tybjaerg-Hansen Angiotensinogen Single Nucleotide Polymorphisms, Elevated Blood Pressure, and Risk of Cardiovascular Disease Hypertension, June 1, 2003; 41(6): 1202 - 1211. [Abstract] [Full Text] [PDF]
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 A. D. Tiago, N. J. Samani, G. P. Candy, R. Brooksbank, E. N. Libhaber, P. Sareli, A. J. Woodiwiss, and G. R. Norton Angiotensinogen Gene Promoter Region Variant Modifies Body Size-Ambulatory Blood Pressure Relations in Hypertension Circulation, September 17, 2002; 106(12): 1483 - 1487. [Abstract] [Full Text] [PDF]
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K. F. Hilgers, C. Delles, R. Veelken, and R. E. Schmieder Angiotensinogen Gene Core Promoter Variants and Non-Modulating Hypertension Hypertension, December 1, 2001; 38(6): 1250 - 1254. [Abstract] [Full Text] [PDF]
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 K. Yanai, K. Hirota, K. Taniguchi-Yanai, Y. Shigematsu, Y. Shimamoto, T. Saito, S. Chowdhury, M. Takiguchi, M. Arakawa, Y. Nibu, et al. Regulated Expression of Human Angiotensinogen Gene by Hepatocyte Nuclear Factor 4 and Chicken Ovalbumin Upstream Promoter-Transcription Factor J. Biol. Chem., December 3, 1999; 274(49): 34605 - 34612. [Abstract] [Full Text] [PDF]
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T. Ishigami, K. Tamura, T. Fujita, I. Kobayashi, K. Hibi, M. Kihara, Y. Toya, H. Ochiai, and S. Umemura Angiotensinogen Gene Polymorphism Near Transcription Start Site and Blood Pressure : Role of a T-to-C Transition at Intron I Hypertension, September 1, 1999; 34(3): 430 - 434. [Abstract] [Full Text] [PDF]
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P. Corvol, A. Persu, A.-P. Gimenez-Roqueplo, and X. Jeunemaitre Seven Lessons From Two Candidate Genes in Human Essential Hypertension : Angiotensinogen and Epithelial Sodium Channel Hypertension, June 1, 1999; 33(6): 1324 - 1331. [Abstract] [Full Text] [PDF]
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T. Niu, J. Yang, B. Wang, W. Chen, Z. Wang, N. Laird, E. Wei, Z. Fang, K. Lindpaintner, J. J. Rogus, et al. Angiotensinogen Gene Polymorphisms M235T/T174M : No Excess Transmission to Hypertensive Chinese Hypertension, February 1, 1999; 33(2): 698 - 702. [Abstract] [Full Text] [PDF]
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 K. Tamura, S. Umemura, N. Nyui, K. Hibi, T. Ishigami, M. Kihara, Y. Toya, and M. Ishii Activation of angiotensinogen gene in cardiac myocytes by angiotensin II and mechanical stretch Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R1 - R9. [Abstract] [Full Text] [PDF]
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