Sage Journals: Discover world-class research

Abstract

Introduction:

The polymorphic angiotensinogen (AGT) gene is one of the most promising candidates for essential hypertension. The aim of this study was to examine the association between the A-6G variant of the AGT gene and the blood pressure response to angiotensin-converting enzyme (ACE) inhibitors in hypertensive subjects.

Methods:

Five hundred and nine mildly to moderately hypertensive subjects received ACE inhibitors for six weeks after a two-week run-in period. AGT genotyping was performed by direct polymerase chain reaction amplification and deoxyribonucleic acid (DNA) nucleotide sequencing from peripheral blood.

Results:

The AA genotype, AG genotype, and GG genotype were present in 301 (59.1%), 186 (36.6%), and 22 (4.3%) of patients, respectively. As compared with patients carrying the AA or AG genotype, those carrying the GG genotype had significantly greater reductions in systolic blood pressure, diastolic blood pressure, pulse pressure and mean arterial pressure (p=0.007, 0.014, 0.027 and 0.005, respectively). Moreover, stepwise multiple linear regression analysis showed that the A-6G genotype was a significant predictor of systolic blood pressure and pulse pressure reductions (p=0.040 and 0.019, respectively).

Conclusion:

Our study indicates that the A-6G variant of the AGT gene may be an important determinant of interindividual variation in the response to ACE inhibitors.

Keywords

Hypertension angiotensinogen angiotensin-converting enzyme inhibitor genotype pharmacogenomics therapeutics

Introduction

Hypertension is a common and complex human disease that causes significant morbidity and mortality worldwide. The etiology and pathogenesis of high blood pressure (BP) are complicated by the varied molecular pathways, genetic polymorphisms, and environmental conditions that converge on BP regulation. The genetic component of hypertension is strong and multiple genes from diverse molecular pathways have been linked to BP. Among these pathways, the renin-angiotensin-aldosterone system (RAAS) is important because of its effects on salt and water homeostasis and autonomic control, as well as vascular structure and function.

Inhibiting the RAAS has long been known as one of the most successful therapies for the management of hypertension. Angiotensin-converting enzyme (ACE) inhibitors are one of the RAAS inhibitors and one of the first-line agents for the treatment of hypertension. However, the BP response to ACE inhibitors varies markedly among individuals and among different ethnic groups.¹ Such variations suggest that the genetic constitution of an individual may play an important role in variation in the response to ACE inhibitor therapy. Candidate genes for the pharmacogenomics of ACE inhibitor therapy include genes in the RAAS pathway. The angiotensinogen (AGT) gene, one of the major structural genes in this pathway, has been associated with hypertension.² A genetic variant A-6G (rs5051) in the proximal promoter region of the AGT gene, an adenine to guanine substitution six base pairs (bp) from the site of transcription initiation, has been significantly associated with elevated plasma AGT levels, AGT gene transcription and essential hypertensive.^3,4 Therefore, we hypothesized that this polymorphism may have the potential to predict the variation in therapeutic response to ACE inhibitors treatment.

As we know, besides systolic blood pressure (SBP) and diastolic blood pressure (DBP), BP is also characterized by its pulsatile and steady components.^5,6 The pulsatile component, estimated by pulse pressure (PP), represents BP variation and is affected by left ventricular ejection fraction, large-artery stiffness, early pulse wave reduction, and heart rate.⁷ The steady component, estimated by mean arterial pressure (MAP), is a function of left ventricular contractility, heart rate, and vascular resistance and elasticity averaged over time.^5,8 In this study, we aimed to investigate whether the A-6G polymorphism of the AGT gene influences the SBP, DBP, PP, and MAP response to ACE inhibitors and the distribution of the polymorphism in Chinese essential hypertensive patients.

Materials and methods

Study population

The material studied comes from the Comparative Study of Hypotensive Efficacy and the Cough Occurrence of Imidapril versus Benazepril,⁹ which is a multicenter prospective trial performed in 20 centers in 12 cities in China. In this study both male and female Chinese Han patients who met the following criteria were included: aged 18–79 years; history of essential hypertension; DBP≥90 mm Hg and ≤109 mm Hg; and SBP<180 mm Hg. The exclusion criteria were isolated systolic hypertension, secondary hypertension, or known renal artery stenosis; congestive heart failure, cerebrovascular accident, transient ischemic attacks or myocardial infarction within the past year; a documented history of unstable angina pectoris within the past six months; clinically important cardiac arrhythmia; uncontrolled diabetes mellitus (fasting plasma glucose>10.0 mmol/l); any clinically important abnormal laboratory finding, such as glutamic–pyruvic transaminase/creatinine twice the upper limit of normal; a history or suspicion of alcohol or drug abuse; pregnant or lactating females; concomitant use of any agent that may cause an alteration of BP; or known hypersensitivity or contraindication to ACE inhibitors. The study complies with the Declaration of Helsinki. All procedures were reviewed and approved by the institutional review board of each participating institution, and written informed consent was obtained from all participants.

A total of 640 patients with essential hypertension participated in our study. All antihypertensive agents were withdrawn before the start of a two-week single-blind placebo run-in period. By use of a double-blind design at the end of the placebo period, a total of 570 qualified patients were allocated randomly to groups receiving either 10 mg benazepril or 5 mg imidapril orally once daily for three weeks. Thereafter patients whose BP was less than 140/90 mm Hg continued with the same dose regimen for another three weeks. In patients whose BP was not adequately controlled (BP≥140/90 mm Hg), the dose of either regimen was doubled for the next three weeks. Four patients in the benazepril group withdrew from the study because of a severe cough during the study. Thus 566 patients completed the trial. The deoxyribonucleic acid (DNA) of 509 patients with complete data was successfully extracted for further analysis. BP was measured by trained doctors or nurses using a mercury sphygmomanometer after the patient had rested for at least 10 min in a seated position and was determined as the mean of three measurements taken 1 min apart. PP was calculated as the difference between SBP and DBP. MAP was calculated as (2DBP + SBP)/3.

Genotyping

The sequence data were obtained from the GenBank database (GenBank accession number NM_000029). The localization of the variant is numbered by reference to the transcription-initiation site as defined previously. The AGT gene A-6G polymorphism was located at position-6 in the promoter region. Genotyping was performed by direct sequencing. Polymerase chain reaction (PCR) primers were designed using Primer3 software. The genomic DNAs from subjects were amplified using 5’-AGAGGTTTTTCAGTCATCACC GT-3’as the forward primer and 5’-ACGGTGATGACTGAAAAACCTCT -3’ as the reverse primer. PCR amplifications were carried out in a total volume of 50 µl with a reaction mixture containing 250 ng genomic DNA, 12.5 pmol of each primer, 10×buffer, 0.6 mmol/l of deoxynucleotide triphosphates (dNTPs) and 2 U Taq DNA polymerase. The PCR amplification conditions included an initial denaturation at 94°C for 2 min, followed by 35 cycles with denaturation at 94°C for 30 s, annealing at 55°C for 30 s, and extension at 72°C for 40 s, followed by a final extension step at 72°C for 5 min. The amplification product (489 bp) contained nucleotides −324 to 165 of the AGT gene, including the polymorphic site mentioned above. The amplified PCR purpose fragment was purified by Wizard PCR Preps DNA Purification Resin (Promega) and then sequenced using the BIG DYE dideoxy-terminator chemistry (Perkin Elmer) on an ABI 3100 DNA sequencer.

Statistical analysis

All analyses were performed using SPSS statistical software (Version 13.0; SPSS, Chicago, Illinois, USA). Allele frequencies were calculated from the genotypes of all subjects. The Hardy-Weinberg equilibrium (HWE) was assessed by chi-square analysis. Continuous data are presented as mean±standard deviation (SD). Differences between groups were tested by chi-square-test for qualitative parameters and by one-way analysis of variance for quantitative parameters. Finally, stepwise multiple linear regression analysis was performed to investigate the possible influence of AGT genotypes on SBP, DBP, PP and MAP reductions in the whole study cohort; sex (where 0 indicates female and 1 indicates male), age, baseline SBP, baseline DBP, baseline heart rate, dose (where 0 indicates no-dose increase and 1 indicates dose increase), and the A-6G genotype (where 0 indicates AA, 1 indicates AG, and 2 indicates GG) were included as independent variables. The entry and removal criteria used were p values of 0.05 for variable entry and p values of 0.10 for variable removal. The associations found in multivariate analyses are reported as multiple regression coefficients (b) (± SD) and as standardized regression coefficients (β). All tests were two-tailed and p<0.05 was considered statistically significant.

Results

Characteristics of the participants

AGT genotypes were determined for all patients. At the end of the placebo period, 250 (49.1%) patients were randomized to receive benazepril and 259 (50.9%) patients to receive imidapril. Table 1 shows the AGT genotype distribution, clinical characteristics, and biochemical parameters of the patients. The AA genotype was observed in 301 patients (59.1%), the AG genotype was observed in 186 patients (36.6%), and the GG genotype was observed in 22 patients (4.3%). Allele frequencies were 77.4% for the A allele and 22.6% for the G allele. The genotype frequencies were shown to be in HWE (x²=1.018679, df=1, p=0.312833).

Table 1.

Subject characteristics by angiotensinogen genotype.

Characteristic	AA	AG	GG	p-value
Sample size (n₁/n₂)	301(147/154)	186(91/95)	22(12/10)	0.873
Dose (no dose-increase/dose-increase)	95/206	53/133	7/15	0.767
Gender (male/female)	172/129	122/64	12/10	0.156
Age (years)	55.9±9.5	54.7±10.4	57.7±10.6	0.247
Body mass index (kg/m²)	26.1±3.4	26.4±2.9	26.1±2.9	0.705
Plasma creatinine (umol/l)	84.5±21.3	83.8±20.6	77.0±15.8	0.264
Plasma sodium (mmol/l)	141.7±4.1	141.9±4.0	141.7±3.8	0.827
Plasma potassium (mmol/l)	4.4±0.4	4.4±0.5	4.5±0.5	0.255
Plasma chloride (mmol/l)	103.7±3.8	103.6±3.2	103.5±3.9	0.905
Fasting plasma glucose (mmol/l)	5.3±1.1	5.3±1.0	5.2±0.6	0.875
Plasma total cholesterol (mmol/l)	5.1±1.0	5.2±1.0	5.0±0.7	0.155
Plasma HDL cholesterol (mmol/l)	1.7±0.8	1.6±0.8	1.6±0.6	0.462
Plasma triglyceride (mmol/l)	1.3±0.4	1.3±0.4	1.4±0.3	0.391
Heart rate (beats/min)
Pretreatment	75.1±8.7	75.3±8.3	75.0±8.0	0.978
Posttreatment	74.4±8.4	75.2±8.5	74.1±6.8	0.558
Systolic blood pressure (mm Hg)
Pretreatment	154.3±12.2	154.7±12.7	158.2±13.3	0.348
Posttreatment	140.6±13.1	140.4±13.0	135.8±8.5	0.241
Diastolic blood pressure (mm Hg)
Pretreatment	96.8±5.3	96.9±5.3	97.9±5.1	0.678
Posttreatment	88.0±7.3	89.1±8.2	85.7±6.3	0.074
Pulse pressure (mm Hg)
Pretreatment	57.4±11.9	57.8±12.1	60.4±112.9	0.526
Posttreatment	52.6±11.2	51.3±11.3	50.0±8.8	0.317
Mean arterial pressure (mm Hg)
Pretreatment	116.0±6.1	116.1±6.3	118.0±6.3	0.340
Posttreatment	105.5±8.0	106.5±8.5	102.4±5.8	0.109

HDL: high-density lipoprotein; n₁: number of patients who received benazepril during the treatment period; n₂: number of patients who received imidapril during the treatment period.

Values are expressed as mean±standard deviation (SD).

Association analyses

In our hypertensive group, there were no significant differences in clinical baseline characteristics among the AA, AG, and GG genotype groups. There were also no significant differences among the three genotype groups in BP, PP or MAP before or after treatment (Table 1). But there was a significant association of AGT A–6G with BP, PP and MAP reductions in response to ACE inhibitors therapy after six weeks treatment (Table 2). The SBP reductions in patients with the AA genotype, AG genotype, and GG genotype were 13.7±11.8 mm Hg, 14.3±13.4 mm Hg, and 22.5±12.1 mm Hg, respectively (p=0.007). The DBP reductions in patients with the AA genotype, AG genotype, and GG genotype were 8.9±6.7 mm Hg, 7.8±7.7 mm Hg, and 12.1±6.7 mm Hg, respectively (p=0.014). The PP reductions in patients with the AA genotype, AG genotype, and GG genotype were 4.8±10.1 mm Hg, 6.5±11.8 mm Hg, and 10.3±10.0 mm Hg, respectively (p=0.027). The MAP reductions in patients with the AA genotype, AG genotype, and GG genotype were 10.5±7.3 mm Hg, 9.9±8.3 mm Hg, and 15.6±7.5 mm Hg, respectively (p=0.005). The reductions in SBP, DBP, PP and MAP were significantly greater in patients carrying the GG compared to AA or AG genotypes (p<0.05). Stepwise multiple linear regression analysis was also performed to investigate the possible influence of the AGT genotypes on the response to therapy with ACE inhibitors. The results showed that the A-6G genotype was a significant predictor of SBP and PP reductions (p=0.040 and 0.019, respectively) (Table 3), which confirmed the association between this variant and the response to ACE inhibitors.

Table 2.

Reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and mean arterial pressure (MAP) in all patients according to the angiotensinogen genotype.

Genotype	n	Fall in SBP (mm Hg)	Fall in DBP (mm Hg)	Fall in PP (mm Hg)	Fall in MAP (mm Hg)
AA	301	13.7±11.8	8.9±6.7	4.8±10.1	10.5±7.3
AG	186	14.3±13.4	7.8±7.7	6.5±11.8	9.9±8.3
GG	22	22.5±12.1	12.1±6.7	10.3±10.0	15.6±7.5
F-value		5.084	4.323	3.621	5.292
p-value		0.007	0.014	0.027	0.005

Values are expressed as mean±standard deviation (SD).

Table 3.

Predictors of systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and mean arterial pressure (MAP) reduction in response to angiotensin-converting enzyme inhibitors.

Variable	b-value	β-value	t-value	p-value
Predictors of SBP reduction
Pretreatment SBP	0.517±0.040	0.512	12.853	<0.001
Dose^a	−8.205±1.089	−0.301	−7.534	<0.001
Pretreatment DBP	0.270±0.096	0.114	2.821	0.005
A-6G genotype^b	1.658±0.807	0.077	2.054	0.040
Predictors of DBP reduction
Pretreatment DBP	0.532±0.059	0.394	8.957	<0.001
Dose^a	−4.912±0.669	−0.318	−7.344	<0.001
Age	0.075±0.030	0.104	2.476	0.014
Predictors of PP reduction
Pretreatment SBP	0.570±0.037	0.654	15.211	<0.001
Dose^a	−3.242±0.923	−0.138	−3.512	<0.001
Pretreatment DBP	−0.336±0.086	−0.164	−3.903	<0.001
Age	−0.172±0.045	−0.157	−3.793	<0.001
A-6G genotype^b	1.606±0.683	0.086	2.352	0.019
Predictors of MAP reduction
Pretreatment SBP	0.178±0.026	0.285	6.754	<0.001
Dose^a	−5.855±0.714	−0.348	−8.200	<0.001
Pretreatment DBP	0.420±0.063	0.285	6.686	<0.001

Results are shown as multiple regression coefficients (b) ±SD and standardized regression coefficients (β) for the effects of the variables selected into the model.

no-dose increase=0, dose increase=1; ^bAA=0, AG=1, GG=2.

Discussion

AGT is the first gene product in the RAAS physiological cascade. The AGT gene polymorphisms have been associated with BP-related phenotypes within different ethnic groups and have been tested for their association with responses to many hypertensive therapies, but the results have been inconsistent.^10,11 The objective of the present study was to examine the association between the A-6G variant of the AGT gene and the response to therapy with ACE inhibitors. To our knowledge, this study appears to be the first prospective study to investigate the association of this polymorphism with PP and MAP response to ACE inhibitors treatment.

The present study showed a lack of association of the A-6G polymorphism with BP in a hypertensive population, because the pretreatment BP was similar in the three genotype groups, which may appear to be consistent with the findings of Marin et al.¹² However, opposite results were reported by Filigheddu et al.¹³ and Brand-Herrmann et al.¹⁴ In this study, the reduction in SBP and DBP after six weeks of ACE inhibitor treatment was significantly greater in patients carrying the GG genotype compared with those carrying the AA or AG genotype. Furthermore, in stepwise multiple regression analysis the AGT genotype was a significant predictor of SBP response to ACE inhibitor treatment. The finding in this study appears reasonable. The acute BP response to ACE inhibitors is mainly due to vasodilation induced by reduction of the plasma concentration of angiotensin II.¹⁵ AGT is the precursor of angiotensin II, and the plasma concentration of AGT may be reflected in differences in the rate of formation of angiotensin II. It can be speculated that the -6G allele is positively correlated with the level of plasma AGT and the patients carrying the GG genotype have increased levels of AGT which are beneficial to ACE inhibitors treatment, because prior studies have found that the -6G allele is associated with increased risk for hypertension in the Chinese populations⁴ and the -6G variant was associated with a higher transcriptional activity than is -6A variant.¹⁶ However, different results were reported by Inoue et al.³ and Sarzani et al.¹⁷ With regard to previous pharmacogenetic studies, there are two such studies that have investigated the association of the A-6G polymorphism and the BP response to monotherapy with ACE inhibitors. Filigheddu et al.¹³ didn’t find an association between the A-6G polymorphism and BP reduction in response to Fosinopril (ACE inhibitors) after four weeks of treatment in 191 white patients with hypertension. Another study, by Marin et al.¹² yielded different results. In 57 white patients with hypertension treated with ACE inhibitors for three years, the subjects carrying the AA genotype had the largest DBP decrease. Two explanations may account for the discrepancy between the previous studies and our present findings. The most likely explanation for such differences is genetic heterogeneity between different populations. The studies by Marin et al.¹² or Filigheddu et al.¹³ were conducted in white hypertensive populations, whereas our study was carried out in a Chinese hypertensive population. There are large differences in G allele frequencies between the present cohort (0.226) and the white hypertensive patients (0.575 or 0.527) studied by Marin et al.¹² or Filigheddu et al.¹³ This different allele frequency may have affected the different results between Chinese and whites. This might somewhat reflect the racial difference. As mentioned above, another reason for inconsistent results among the study by Marin et al.¹² or Filigheddu et al.¹³ and the present findings could be the differences in population characteristics, selection criteria of the sample, agents used, study protocols, study durations, and outcome measures. These differences are likely to influence their phenotypes and may have a bearing on the study results.

PP is a predictor of cardiovascular disease, and genes likely influence PP levels.^18–20 Few studies thus far have examined the relationship between AGT genotypes and PP. The study performed by Lynch et al.²⁰ demonstrated that women with the GG genotype had a lower PP, while men with the GG genotype had a higher PP, compared with those carrying an A allele in a hypertensive cohort. However, in the present study, we found no significant differences in PP between individuals with different A-6G genotypes in our hypertensive patients and there were also no such differences in PP in the analysis stratified by sex (data not shown). As we know, PP was used as a measurement of arterial stiffness. Increased arterial stiffness is recognized as a risk factor for cardiovascular and cerebrovascular events. Several methods exist to measure arterial stiffness, of which PP is the simplest. Although PP is not the most sensitive method to measure arterial stiffness, it has the advantage over other methods that it has been recognized as a risk factor for cardiovascular disease (CVD) and stroke.^21,22 In our study, the reduction in PP after six weeks of ACE inhibitor treatment was significantly greater in patients carrying the GG compared with AA or AG genotypes, and the result of the stepwise multiple regression analysis also showed that the AGT genotype was a significant predictor of the PP response to ACE inhibitor treatment. As we know, components of the RAAS are expressed in vascular smooth muscle cells. Local production of AGT occurs in the media in response to arterial injury,²³ and AGT was shown to have direct effects on vascular wall remodelling in vivo in a rat model.²⁴ So, our results suggest that genetic variation in AGT promoter area may primarily affect arterial stiffness, and therefore PP under ACE inhibitor therapy.

MAP, which is highly correlated with either SBP or DBP, is the steady flow of blood through the aorta and its arteries and equals the cardiac output multiplied by vascular resistance.⁵ Dyer et al. found that the steady component of BP (highly correlated with MAP) was more strongly associated with CVD risk than PP in four Chicago epidemiological studies.²⁵ There are so far very few studies that have examined the relationship between AGT genotypes and MAP. The present study showed a lack of association of the A-6G polymorphism with baseline MAP in a hypertensive population, which may appear to be consistent with the findings of Bhuiyan et al.²⁶ However, in our study, the reduction in MAP after six weeks of ACE inhibitors treatment was significantly greater in patients carrying the GG compared with AA or AG genotypes. To the best of our knowledge, this study has, for the first time, found that the A-6G polymorphism was related to the PP reduction (mentioned above) and MAP reduction in response to antihypertensive drugs. We, therefore, speculated that the patients carrying the GG genotype may derive extra benefits with the use of ACE inhibitors.

A limitation of our study is the relatively short therapeutic duration. However, with the significant reduction in BP after six-week treatment, we had sufficient statistical power to confirm the relationship between A-6G variant of the AGT gene and interindividual variation in the response to ACE inhibitors. Another limitation of our study is that the patients were only recruited from the Chinese Han population. Studies in other ethnic populations and in larger cohorts may be needed before final conclusions can been drawn.

In conclusion, in this prospective study, positive and continuous associations were observed between the SBP, DBP, PP, and MAP response to ACE inhibitors and A-6G variant of the AGT gene in hypertensive subjects. Our observation might support the view that interindividual variation in the efficacy of antihypertensive medications may be influenced by genetic factors. This implies the advantage of genotyping for selecting the optimal antihypertensive treatment for the individual patient.

Footnotes

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

This study was supported by National Natural Science Foundation of China (grant number 81273599, 81170246); Shanghai Pujiang Talents Program of Shanghai Science and Technology Committee (grant number 11PJ1408300); and the China Postdoctoral Science Foundation (grant number 20060390194).

References

Koopmans

Insel

Michel

. Pharmacogenetics of hypertension treatment: A structured review. Pharmacogenetics 2003; 13: 705–713.

Johnson

Newton-Cheh

Chasman

. Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. Hypertension 2011; 57: 903–910.

Inoue

Nakajima

Williams

. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Inves 1997; 99: 1786–1797.

Shen

Yan

. Association of polymorphisms in the AGT gene with essential hypertension in the Chinese population. J Renin Angiotensin Aldosterone Syst 2012; 13: 282–288.

Safar

. Pulse pressure in essential hypertension: Clinical and therapeutical implications. J Hypertens 1989; 7: 769–776.

Darne

Girerd

Safar

. Pulsatile versus steady component of blood pressure: A cross-sectional analysis and a prospective analysis on cardiovascular mortality. Hypertension 1989; 13:392–400.

Franklin

Gustin

IV Wong

. Hemodynamic patterns of age-related changes in blood pressure: The Framingham Heart Study. Circulation 1997; 96: 308–315.

Benetos

Laurent

Asmar

. Large artery stiffness in hypertension. J Hypertens Supp 1997; 15: S89–S97.

Imidapril and Benazepril Clinical Study Cooperation Unit. Comparative study of hypotensive efficacy and the cough occurrence of imidapril versus benazepril. Chin J Cardiol 2004; 32: 304–307.

10.

Jeng

. Left ventricular mass, carotid wall thickness, and angiotensinogen gene polymorphism in patients with hypertension. Am J Hypertens 1999; 12: 443–450.

11.

Mellen

Herrington

. Pharmacogenomics of blood pressure response to antihypertensive treatment. J Hypertens 2005; 23: 1311–1325.

12.

Marin

Julve

Chaves

. Polymorphisms of the angiotensinogen gene and the outcome of microalbuminuria in essential hypertension: A 3-year follow-up study. J Hum Hypertens 2004; 18: 25–31.

13.

Filigheddu

Argiolas

Bulla

. Clinical variables, not RAAS polymorphisms, predict blood pressure response to ACE inhibitors in Sardinians. Pharmacogenomics 2008; 9: 1419–1427.

14.

Brand-Herrmann

Köpke

Reichenberger

. Angiotensinogen promoter haplotypes are associated with blood pressure in untreated hypertensives. J Hypertens 2004; 22: 1289–1297.

15.

Juillerat

Nussberger

Ménard

. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension 1990; 16: 564–572.

16.

Tsai

Fallin

Chiang

. Angiotensinogen gene haplotype and hypertension: Interaction with ACE gene I allele. Hypertension 2003; 41: 9–15.

17.

Sarzani

Bordicchia

Marcucci

. Angiotensinogen promoter variants influence gene expression in human kidney and visceral adipose tissue. J Hum Hypertens 2010; 24: 213–219.

18.

Benetos

Rudnichi

Safar

. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension 1998; 32: 560–564.

19.

Bangalore

Messerli

Franklin

. Pulse pressure and risk of cardiovascular outcomes in patients with hypertension and coronary artery disease: An INternational VErapamil SR-trandolapril STudy (INVEST) analysis. Eur Heart J 2009; 30:1395–1401.

20.

Lynch

Arnett

Davis

. Sex-specific effects of AGT-6 and ACE I/D on pulse pressure after 6 months on antihypertensive treatment: The GenHAT study. Ann Hum Genet 2007; 71: 735–745.

21.

Lewington

Clarke

Qizilbash

. Age-specific relevance of usual blood pressure to vascular mortality: A meta analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913.

22.

Okada

Iso

Cui

. Pulse pressure is an independent risk factor for stroke among middle-aged Japanese with normal systolic blood pressure: The JPHC study. J Hypertens 2011; 29: 319–324.

23.

Rakugi

Jacob

Krieger

. Vascular injury induces angiotensinogen gene expression in the media and neointima. Circulation 1993; 87: 283–290.

24.

Brand

Lamandé

Sigmund

. Angiotensinogen modulates renal vasculature growth. Hypertension 2006; 47: 1067–1074.

25.

Dyer

Stamler

Shekelle

. Pulse pressure, III: Prognostic significance in four Chicago epidemiologic studies. J Chron Dis 1982; 35: 283–294.

26.

Bhuiyan

Chen

Srinivasan

. G-6A polymorphism of angiotensinogen gene modulates the effect of blood pressure on carotid intima-media thickness. The Bogalusa Heart Study. Am J Hypertens 2007; 20: 1073–1078.

A core promoter variant of angiotensinogen gene and interindividual variation in response to angiotensin-converting enzyme inhibitors

Abstract

Introduction:

Methods:

Results:

Conclusion:

Keywords

Introduction

Materials and methods

Study population

Genotyping

Statistical analysis

Results

Characteristics of the participants

Association analyses

Discussion

Footnotes

Conflict of interest

Funding

References