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Circulation. 2007;115:725-732
Published online before print January 29, 2007, doi: 10.1161/CIRCULATIONAHA.106.642058
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(Circulation. 2007;115:725-732.)
© 2007 American Heart Association, Inc.

Hypertension

Association Between Angiotensinogen, Angiotensin II Receptor Genes, and Blood Pressure Response to an Angiotensin-Converting Enzyme Inhibitor

Xiaowen Su, MD; Liming Lee, MD, MPH; Xiaohui Li, MD; Jun Lv, PhD; Yonghua Hu, MD; Siyan Zhan, MD, PhD; Weihua Cao, MD, MPH; Ling Mei, MD; Yong-Ming Tang, PhD; Dai Wang, PhD; Ronald M. Krauss, MD; Kent D. Taylor, PhD; Jerome I. Rotter, MD; Huiying Yang, MD, PhD

From the Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, Calif (X.S., X.L., L.M., Y.-M.T., D.W., K.D.T., J.I.R., H.Y.); Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China (L.L., J.L., Y.H., S.Z., W.C.); and Children’s Hospital Oakland Research Institute, Oakland, Calif (R.M.K.).

Correspondence to Huiying Yang, MD, PhD, Medical Genetics Institute, 665 West Tower, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 (e-mail huiying.yang{at}cshs.org) or Liming Lee, MD, MPH, Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Dongdan 3 tiao 9 hao, Beijing 100730, PR China (e-mail lmlee@pumc.edu.cn).

Received May 25, 2006; accepted November 30, 2006.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background— To identify the genetic contribution to the variation in blood pressure (BP) response to angiotensin-converting enzyme inhibitors (ACEIs), single-nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT), angiotensin receptor 1 (AGTR1), and angiotensin receptor 2 (AGTR2) genes were evaluated for their association with BP response to ACEI in Chinese patients with hypertension in a 2-stage design.

Methods and Results— We selected 1447 hypertensive patients from a 3-year benazepril postmarket surveillance trial and genotyped them for 14 SNPs in the AGT, AGTR1, and AGTR2 genes. The AGT rs7079 (C/T) SNP (3'-untranslated region) was significantly associated with the response of diastolic BP to benazepril (diastolic BP response: –7.4 mm Hg for subjects with the CC genotype, –8.9 mm Hg for CA, and –10.1 mm Hg for AA; P=0.001). Although there was no association of individual SNPs in the AGTR1 gene, there was a graded response between common haplotypes and systolic BP reduction in the order of haplotype 2 (H2)/lack of haplotype 3 (non-H3) (–13.6 mm Hg) > non-H2/non-H3 (–10.9 mm Hg) > H3/non-H2 (–6.6 mm Hg) (P=0.004). The total variations in response to ACEI therapy that were explained by the AGT SNP and AGTR1 haplotype groups were 13% for systolic and 9% to 9.6% for diastolic BP, respectively.

Conclusion— AGT SNP rs7079 and AGTR1 haplotypes were associated with BP reduction in response to ACEI therapy in hypertensive Chinese patients. This will be useful in future studies, providing genetic markers to predict the hypertensive response to ACEI therapy.


Key Words: angiotensin-converting enzyme inhibitors • angiotensinogen • receptors, angiotensin • polymorphism, single nucleotide • hypertension


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Blood pressure (BP) control has been associated with an approximately 40% reduction in the risk of stroke and an approximately 15% reduction in the risk of myocardial infarction.1 Angiotensin-converting enzyme inhibitors (ACEIs) are one of the first-line agents for the treatment of hypertension.2 By blocking the active site of angiotensin-converting enzymes, these agents decrease angiotensin II (AngII) levels, thereby lowering BP.3,4 However, the BP response to ACEI varies markedly among individuals and among different ethnic groups.5,6 Such variations suggest that the genetic constitution of an individual may play a major role in the BP response to ACEI therapy.

Candidate genes for the pharmacogenetics of ACEI therapy include genes in the renin–angiotensin pathway. The angiotensinogen (AGT) gene, one of the major structural genes in this pathway, has been associated with hypertension,7 and the AGT single-nucleotide polymorphisms (SNPs) M235T(rs699), M174T(rs4762), and A-6G(rs5051) have been associated with serum AGT levels.8–13 AGT SNPs also have been associated with BP-related phenotypes within different ethnic groups14,15 and have been tested for their association with responses to many hypertensive therapies such as diuretics, ß-blockers, angiotensin receptor blockers, calcium channel blockers, and ACEIs, but the results have been inconsistent.16 The actions of AngII are mediated by AngII receptors. The major receptor is the AngII type I receptor (AGTR1), which mediates the major biological actions of AngII, including vascular contraction, pressure responses, renal tubular sodium transport, and aldosterone secretion.17,18 Another receptor, the AngII type II receptor (AGTR2), is the minority subtype with relatively lower expression in adult tissue.19 AGTR2 is thought to be a vasodilator and antigrowth effector.20 AGTR121–23 and AGTR224,25 variants have been associated with hypertension and with responses to antihypertensive therapy, but these results also have been inconsistent.26–29

Clinical Perspective p 732

The aim of the present study was to test several AGT, AGTR1, and AGTR2 SNPs for their association with BP reduction in response to ACEIs, analyzing SNPs as well as haplotypes in a large ACEI postmarket surveillance trial among the Chinese population.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Subjects
Subjects were recruited from the 3-year postmarketing surveillance of benazepril, an ACEI, within the Chinese Community-Based Comprehensive Prevention and Control of Hypertension project,30 a study of 34 770 permanent residents ≥35 years old in the Nanshi District of Shanghai, China. All participants in the Chinese Community-Based Comprehensive Prevention and Control of Hypertension project were screened for BP and medical history by a standard questionnaire. Baseline BP was measured in the morning (9 to 12 AM) for most of the patients (80%), using standard methods. Hypertension was defined as mean diastolic BP (DBP) ≥90 mm Hg, mean systolic BP (SBP) ≥140 mm Hg, or current use of antihypertensive medication. Exclusion criteria included recent myocardial infarction, stroke, uncontrolled angina within the past 3 months, and severe liver or renal disease. Hypertensive patients with written informed consent were recruited into this surveillance trial and were observed for 3 years.

Benazepril hydrochloride (Lotensin; Novartis AG, Basel, Switzerland) was given to participants to control BP to less than 140/90 mm Hg. The initial daily dosage was either 5 mg for patients with mild hypertension or 10 mg for patients with moderate and severe hypertension, and patients were then evaluated every 2 weeks for 8 weeks to obtain the target BP with the minimum required dose. At each follow-up visit, if the target BP level had not been reached, an increment of 5 mg/d was added until the target BP was achieved or the dosage reached 20 mg/d (Table 1). For those who still did not reach the BP target level at 20 mg/d, dihydrochlorothiazide was added. Patients were considered nonresponders to trial medication if they had not reached the target BP level at the end of 12 weeks after the above treatment; these patients were excluded from the trial. As a result, 1831 patients were included in the trial. The blood samples of 1831 subjects were collected at the first visit, tested for serum creatinine and blood urea nitrogen, and stored for deoxyribonucleic acid extraction. Of these, a subset (n=1501) had sufficient deoxyribonucleic acid samples for genotyping. There was no significant difference between the subjects with and without deoxyribonucleic acid samples for gender, age, smoking, body mass index, baseline BP, dose, or BP reduction (data not shown). The 54 patients treated with dihydrochlorothiazide were excluded. Reduction in BP was defined as the difference between the baseline BP and BP from the last visit for patients without any adverse effects. For patients with adverse effects, and to reduce confounding attributable to changes in the dose of benazepril to manage patient health, the BP from the last visit before the onset of the adverse effect was used to calculate reduction. All research was approved by the institutional review boards of Cedars-Sinai Medical Center and Peking University.


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  		TABLE 1. Comparing Clinical Characteristics Between the Exploratory Versus Confirmatory Samples

SNP Selection and Genotyping
As shown in Figure 1, 14 SNPs from AGT, AGTR1, and AGTR2 were selected (1) to tag common genetic variation in the Caucasian and African American populations using resequencing information generated at the University of Washington, Seattle, for an associated project, the Pharmacogenetics of Atherosclerosis Risk of Cardiovascular disease (http://droog.gs.washington.edu/parc) (r2≥0.8 in either population; minor allele frequency ≥0.05; at the time of this study, no equivalent data were available for any Chinese populations),31 (2) to test SNPs previously reported to be associated with hypertension,* and/or (3) to include SNPs in the promoter regions. Genotyping was performed using TaqMan technology, as previously described.36 The sequences of all primers and probes involved are available on request. Each SNP was in Hardy–Weinberg equilibrium (data not shown).


Figure 1181201
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  		Figure 1. Angiotensinogen (AGT), angiotensin II receptor 1 (AGTR1), and angiotensin II receptor 2 (AGTR2) gene structure and selected single-nucleotide polymorphisms (SNPs). Four SNPs from AGT, 7 SNPs from AGTR1, and 3 SNPs from AGTR2 genotyped in this study are shown with their location within the genes and their corresponding polymorphic bases. The exons are denoted as boxes; hollow sections denote noncoding regions, and solid sections denote coding regions.

Statistical Analyses
To control for type I error attributable to multiple testing, analysis was conducted in 2 phases: First, all markers and haplotypes were tested in an exploratory sample (n=733); then, positive results were tested in a confirmatory sample (n=714). The 2 samples were randomly selected from the total of 1447 subjects.

For quantitative variables, the univariate comparisons between groups were tested by the Student t test when variables had a normal distribution, or by nonparametric Wilcoxon rank test when variables deviated from normal distribution. We used the {chi}2 test to compare proportions of qualitative variables between groups. Pairwise linkage disequilibrium (LD; D' and r2) between SNPs were calculated with Haploview software.37 Univariate and multiple regression analyses were performed for single SNPs as well as for haplotypes with a frequency ≥3%. Further analysis of AGTR1 haplotype 2 (H2) and haplotype 3 (H3) was conducted by dividing subjects into 3 groups: H2 present/H3 absent (H2/non-H3), H3 present/H2 absent (H3/non-H2), and both H2 and H3 absent (non-H2/non-H3). Because of small sample size, H2/H3 heterozygotes (n=9 from exploratory set, n=7 from confirmatory set) were deleted from further analysis. The association of response was then tested using the groups as ordinal variables: H2/non-H3=–1, non-H2/non-H3=0, and H3/non-H2=+1. BP reduction was used as the outcome variable for multiple regression and gender, age, baseline BP, maximal dosage of benazepril, and kidney function (blood urea nitrogen and creatinine) as covariates. Covariates with significance <0.05 in stepwise regression were retained in the final model. R2 was calculated to estimate the proportion of explained variation of the outcome variable as a function of the independent variable in the regression model. To test the interactions between gender and haplotypes, analyses by the stratum of gender were also performed, and the interaction term of gender-by-haplotypes was added in the regression model. The probability value of the coefficient of SNPs/haplotypes in the regression model was estimated and presented in the results. All statistical analyses were performed with SAS statistical software (V8, SAS Institute, Cary, NC).

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
Clinical Characteristics
The randomly divided exploratory group (n=733) and confirmatory group (n=714) were similar in demographic and clinical characteristics (Table 1) as well as allele (Table I) and haplotype frequencies (Table 2).


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  		TABLE 2. Haplotype Structure and Frequencies of the AGT and AGTR1 Genes

SNPs and Haplotypes of AGT, AGTR1, and AGTR2
AGT
All 4 AGT SNPs were in strong LD (D'≥0.9, P<0.001); because rs5051 and rs699 were in complete LD, only results from rs699 are presented here. Four haplotypes comprise approximately 99% of observed haplotypes (Table 2).

AGTR1
Two groups of SNPs were in tight LD with each other (rs1492078, rs2638362, and rs2640543; and rs389566, rs275649, rs5182, and rs5186; Table II). Six haplotypes comprise approximately 85% of observed haplotypes (Table 2).

AGTR2
All 3 SNPs were in strong LD (D'>0.97, P<0.001). Because AGTR2 is located on the X chromosome,38 haplotypes were constructed separately for males and females, and similar frequencies were observed for each gender. Three haplotypes comprise 97% of observed haplotypes (Table 3).


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  		TABLE 3. Haplotype Structure and Frequencies of the AGTR2 Gene

AGT SNP rs7079 and BP Reduction
Under both a dominant and additive model for association analysis of single SNPs, in the exploratory group, AGT SNP rs7079 was associated with a reduction in DBP in response to ACEI therapy: CC homozygotes showed a decreased DBP reduction compared with those with either AA or AC genotypes (Table 4). This difference was statistically significant after adjusting for baseline BP, gender, age, kidney function, and benazepril dose. This association was further observed in the confirmatory group and in both sets combined (Figure 2A). Furthermore, as shown in Figure 2A, the same trend was found for both SBP and DBP response, but the difference for SBP was only statistically significant in the total sample (P=0.04). The total variation of the SBP reduction explained by rs7079 was 13%; for DBP reduction, it was 9.6% (R2 in total sample). There was no association between BP reduction in response to ACEI therapy and for any of the AGTR1 or AGTR2 individual SNPs (data not shown).


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  		TABLE 4. Association between AGT Gene SNPs and BP Reduction Response to ACEI Therapy in Exploratory Set


Figure 2181201
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  		Figure 2. Association of individual angiotensinogen single-nucleotide polymorphism C11537A (rs7079) (A) and haplotype 2 (B), with blood pressure (BP) reduction response to angiotensin-converting enzyme inhibitor therapy in exploratory, confirmatory, and total study sets. Data are presented as mean of the reduced blood pressure. N indicates the number of individuals with genotypes CC, CA, and AA, or haplotype 2 carriers and non–haplotype 2 carriers. Probability values shown here are from multiple regression analysis, adjusting for other covariates including baseline blood pressure.

Haplotypes and BP Reduction
AGT
As shown in Table 5, among the 4 common haplotypes in the AGT gene, H2 showed a trend toward a greater DBP reduction in response to ACEI therapy (P=0.086) in the exploratory group and an association in the confirmatory group (P=0.038; combined P=0.019; Figure 2B). H2 is the only haplotype with allele A of rs7079, but it shows a less significant association with BP reduction; thus, the H2 association may be secondary to the effect of rs7079 allele A or to an untested allele in strong LD with allele A.


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  		TABLE 5. Association of AGT and AGTR1 Haplotypes in Exploratory Set With BP Reduction Response to ACEI Therapy

AGTR1
AGTR1 H2 and H3 seemed to be associated with BP reduction (H2 with SBP, P=0.04; H3 with DBP, P=0.04; Table 5). After adjusting for baseline BP, the probability values of the associations between H2 carriers and SBP reduction and between H3 carriers and DBP reduction were of borderline statistical significance (P=0.09 and 0.08, respectively). To estimate the effects of both AGTR1 H2 and AGTR1 H3 compared with those of non-H2 and non-H3 carriers, we divided the subjects into 3 groups based on their combinations of haplotypes (details in Methods), and we performed multiple regression analysis using the 3 AGTR1 haplotype groups as ordinal variables and adjusting for other covariates, including baseline BP (Figure 3). In both the exploratory and confirmatory analysis, the AGTR1 haplotype combination was associated with a reduction of SBP (exploratory, P=0.05; confirmatory P=0.045; combined P=0.004; Figure 3, upper panel). In the total sample, the means (±SD) of SBP reduction for each group were 13.6±16.7 mm Hg (n=219) for the group with H2, 10.9±15.4 mm Hg (n=1112) for the group with neither H2 nor H3, and 6.6±16.0 (n=100) for the group with H3. A similar trend in DBP reduction was observed with the same haplotype groups, but this observation was statistically significant only when the subjects were combined (P=0.035; Figure 3, lower panel). In this analysis, the AGTR1 haplotype groups explained 13% of the total reduction in SBP and 9% of the total reduction of DBP in response to ACEI therapy. In addition to baseline SBP and BP reduction, only gender exhibited a significant difference among the 3 AGTR1 groups (P=0.002) (Table III). An interaction test demonstrated that gender did not interact with BP reduction among the 3 AGTR1 groups (all P>0.15, data not shown). Thus, we concluded that the effect of the AGTR1 haplotypes was present even after adjustment for any possibly confounding variables.


Figure 3181201
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  		Figure 3. Association of angiotensin II receptor 1 haplotype 2 (H2), haplotype 3 (H3) haplotypes with blood pressure reduction response to angiotensin-converting enzyme inhibitor therapy in exploratory, confirmatory, and total study sets. Data are presented as mean of the reduced blood pressure. N indicates the number of haplotype groups: H2/non-H3, H3/non-H2, and non-2/non-H3 (detailed in Methods). Probability values shown here are from multiple regression analysis, adjusting for other covariates including baseline blood pressure.

AGTR2
The presence of AGTR2 H2 showed a trend toward SBP response in females in the exploratory set (Table 6), but this association was not observed in the confirmatory set (data not shown).


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  		TABLE 6. Association of AGTR2 Haplotype in Exploratory Set With BP Reduction Response to ACEI Therapy


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In the present study of subjects undergoing 3 years of benazepril therapy, we have observed an association between response to ACEI therapy and AGT SNP rs7079 and 2 AGTR1 haplotypes (H2 and H3). These associations remained after adjustment for multiple comparisons as well as for potential confounding factors including baseline BP. Multiple regression analysis showed that these associations accounted for a sizable amount of the variation in response to ACEI therapy, in the range of 13% of SBP and 9% to 9.6% of DBP.

We have confirmed previously reported linkage disequilibrium across AGT between 2 SNPs (rs5051 in the promoter and rs699 in exon 2).39 The SNP rs699 has been associated with lowered BP in response to ACEI treatment in 1 study,27 but not in other studies.40,41 In this study, 3 AGT SNPs (rs5051, rs699, and rs4762) were not associated with BP response to ACEIs; however, the minor allele frequencies of these SNPs in this Chinese population were considerably lower than in other populations (rs4762/T207M, 0.09 versus 0.19; approximately 0.18 versus 0.39 to 0.46 for rs699/T268M and rs5051/–6A–>G).16 However, AGT was associated here with response to ACEI therapy: AGT SNP rs7079 was associated with DBP reduction. This SNP describes C-to-A polymorphism and is in the 3'-untranslated region of the AGT gene. Around this SNP, by using the Transcription Element Search System (TESS v4.0; http://www.cbil.upenn.edu/tess), a ubiquitous factor AP4–binding site was observed when the sequence contained the C allele. However, it lost the AP4-binding site when the sequence was replaced by the A allele in this site. Thus, the potential function of the SNP might have a relationship with a potential binding site for transcription factor AP4.

AGTR1 SNP A-1166C (rs5186) has been the most widely studied and has been associated with end-point phenotypes (eg, hypertension and myocardial infarction),21,34,42 but the results have been inconsistent.22,43 This SNP also has been associated with SBP response to diuretic therapy in black women.26 The current study did not observe an association between this SNP and response to ACEIs, but again, the C allele frequency is lower in the Chinese population (0.06 versus 0.29 in whites).35,44 Thus, the negative result with rs5186 may be attributable to this lower frequency. Because 2 common AGTR1 haplotypes (H2 and H3) were observed to be associated with BP reduction in this gene, AGTR1 variation may also play a role in ACEI response in Chinese patients. Chinese-specific variants may remain to be discovered by sequencing H2 and H3 and looking for variants in strong linkage disequilibrium with the tag SNPs for these haplotypes. Alternatively, the known AGTR1 variation may interact with the genetic background of this Chinese population in determining BP and response to ACEIs. These results further illustrate that a haplotype approach may be useful for testing the association of a phenotype with a gene when all of the genetic variations within a particular population may be unknown.

The major limitation of this study is that it was a postmarketing study rather than a randomized clinical trial, and thus it was not possible to control many confounding factors. For example, in 1501 patients analyzed, although 557 (37%) of patients were on drug therapy before enrolling in this study, their BP was not controlled at an optimum level, such that the mean baseline BP in this group was 149/93 mm Hg, and there was a subsequent, further mean reduction of 9.2 (SBP) and 6.7 (DBP) mm Hg during the surveillance. There was no effect on the analysis presented here when these 557 subjects were removed (data not shown), but a potential consequence of including subjects without a run-in period may be a reduction in the power to detect a genetic effect attributable to increased noise in the dataset. However, this reduction in power would interfere with gene-finding efforts, leading to underestimation of the observed genetic effect reported here.

In conclusion, we expect that the AGT and AGTR1 associations observed here, if confirmed, will be useful for predicting BP responses to ACEI treatment and may lead to the identification of further pharmacogenetic variations specific to Chinese populations.


*    Acknowledgments
 
This work was supported by National Heart, Lung, and Blood Institute grant HL69757, the Pharmacogenetics Network for Cardiovascular Risk Therapy (PARC) study, and the Cedars-Sinai Board of Governors’ Chair in Medical Genetics (Dr Rotter).

Disclosures

None.


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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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CLINICAL PERSPECTIVE

The implication of this study is that variations in an individual’s genes determine his or her responsiveness to a specific antihypertensive agent. This pharmacogenetic study originated from the Chinese Community-Based Comprehensive Prevention and Control of Hypertension project, a large-scale project with 34 770 participants. The results reported here reveal that the candidate genes for primary hypertension, namely, variants of AGT and the AGTR1 genes, are involved in an individual’s response to angiotensin-converting enzyme therapy. These data yield several provocative results for a hypertension pharmacogenetic study. First, because the study was designed with a TagSNP approach, using some of the most common variants in the genes as an efficient way to screen for the effect of the entire gene, the actual responsible genetic variants need to be further delineated in the Chinese population and, likely, in other populations as well. Second, although these AGT single-nucleotide polymorphism or AGTR1 haplotype associations accounted for a sizeable amount of variation in response to angiotensin-converting enzyme therapy (in the range of 13% of systolic blood pressure and 9% to 9.6% of diastolic blood pressure), there is clearly room for other genes and their variants to be additional determinants of the response. Finally, identifying these genetic variants and understanding their mechanisms may provide insight into the development of new therapies. In summary, variants of the AGT and the AGTR1 genes are associated with blood pressure response to angiotensin-converting enzyme therapy. If confirmed, they will be useful for predicting blood pressure response to angiotensin-converting enzyme treatment, and they may lead to the identification of further pharmacogenetic variation, not only for Chinese populations, but in other populations as well.


*    Footnotes
 
The online-only Data Supplement, consisting of Tables I through III, can be found at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.106.642058/DC1.

*References 3, 10–13, 21, 22, 24, 25, 27, 28, and 32–35. Back


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