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(Hypertension. 1996;28:1076-1080.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin II Type 1 Receptor A/C¹¹⁶⁶ Polymorphism

Relationships With Blood Pressure and Cardiovascular Structure

Maurizio Castellano; Maria Lorenza Muiesan; Marina Beschi; Damiano Rizzoni; Angelo Cinelli; Massimo Salvetti; Gianfranco Pasini; Enzo Porteri; Giorgio Bettoni; Roberto Zulli; Enrico Agabiti-Rosei

the Department of Scienze Mediche, University of Brescia (Italy).

Correspondence to Maurizio Castellano, MD, Scienze Mediche, University of Brescia, c/o 1 Medicina, Spedali Civili, 25100 Brescia, Italy. E-mail castell@master.cci.unibs.it.

	Abstract

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The angiotensin II type 1 (AT₁) receptor has a key role in mediating the vasoconstrictor and growth-promoting effects of angiotensin II. It has been reported that a polymorphism of the AT₁ receptor gene (an A/C transversion at position 1166) may be associated with cardiovascular phenotypes, such as arterial blood pressure and aortic stiffness, that underlie a condition of increased cardiovascular risk. We examined a sample of 212 subjects randomly selected from a general population in northern Italy to investigate the role of AT₁ receptor gene polymorphism in the regulation of blood pressure and cardiovascular growth. We measured blood pressure (both clinic and 24-hour ambulatory recording), left ventricular mass (echocardiography), and carotid artery wall thickness (B-mode ultrasound); we assessed the AT₁ receptor genotype by polymerase chain reaction and allele-specific oligonucleotide hybridization. Blood pressure values were lower in CC homozygotes than in heterozygotes and AA homozygotes; the difference was statistically significant for clinic measurements (mean difference for mean blood pressure, -6.6 mm Hg, P=.01; 95% confidence interval, -1.6 to -11.7 mm Hg) but not for ambulatory blood pressure measurements. CC homozygotes also presented a lower incidence of a positive family history of hypertension (P=.027). No statistically significant differences among AT₁ receptor A/C¹¹⁶⁶ genotypes were observed for left ventricular mass or carotid artery wall thickness. We conclude that the present study does not support a major role of the AT₁ receptor gene A/C¹¹⁶⁶ polymorphism as a marker of conditions associated with increased cardiovascular risk.

Key Words: receptors, angiotensin • polymorphism, genetic • blood pressure • hypertrophy

	Introduction

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Over the last few years, several associations between renin-angiotensin system gene polymorphisms and cardiovascular phenotypes (including blood pressure [BP], left ventricular mass, carotid wall thickness, and the occurrence of ischemic heart disease) have been proposed and then confirmed or denied by subsequent investigation. The angiotensin II type 1 (AT₁) receptor appears to be the primary receptor that mediates the vasoconstrictor and growth-promoting effects of angiotensin II in humans.¹ Several diallelic polymorphisms have been detected in the coding and 3' untranslated regions of this gene² ; none of them is functionally relevant, but some associations with cardiovascular phenotypes have been reported for one variant, an A/C transversion located at the 5' end of the 3' untranslated region (position 1166 according to Reference 3).

A significant increase in allelic frequency of C¹¹⁶⁶ was observed by Bonnardeaux et al² in hypertensive subjects with a positive family history of hypertension compared with normotensive control subjects. In a recent study, Benetos et al⁴ did not confirm such a relationship of the AT₁ A/C¹¹⁶⁶ with BP but reported an association with aortic pulse-wave velocity, an accepted index of aortic stiffness. Furthermore, in the Etude Cas-Temoins sur l'Infarctus du Myocarde (ECTIM) study population, Tiret et al⁵ found a significant interaction between an angiotensin-converting enzyme insertion/deletion polymorphism and the AT₁ A/C¹¹⁶⁶ gene polymorphisms: The odds ratio for myocardial infarction associated with the angiotensin-converting enzyme DD genotype was fourfold higher in AT₁ CC homozygotes than in AA homozygotes. No data have been reported thus far on the possible influence of AT₁ A/C¹¹⁶⁶ gene polymorphism on cardiovascular structural alterations.

In the present study, we further evaluate the relationship of the AT₁ A/C¹¹⁶⁶ gene polymorphism with BP, as determined by both clinic and ambulatory BP measurements, in a middle-aged, general population sample; in addition, we also investigate possible associations with left ventricular mass and carotid wall thickness.

	Methods

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Study Population
This study examined the general population of Vobarno, a town in northern Italy with a population of approximately 7000. Three-hundred and sixty-nine subjects between the ages of 50 and 64 years, randomly selected from the electoral roll, were invited to enter the study; in 212 subjects (38% of the eligible population), we were able to perform a satisfying assessment of left ventricular mass and carotid wall thickness and to determine the AT₁ A/C¹¹⁶⁶ genotype. All the subjects gave informed consent to the study procedures. There were 17 sibships in this sample population (16 pairs and 1 trio), and 47 individuals received chronic treatment for hypertension or ischemic heart disease with drugs potentially influencing BP and left ventricular mass (diuretics, ß-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, or ₁-blockers).

Assessment of Cardiovascular Risk Factors
In each subject, a careful medical history was collected by a physician using a standardized questionnaire; in particular, parental history of hypertension, ischemic heart disease (myocardial infarction and/or angina pectoris), stroke, dyslipidemia, and diabetes mellitus was carefully investigated. Serum glucose, total serum cholesterol, serum triglyceride, and serum uric acid concentrations were measured by conventional assays.

Echocardiography
Echocardiographic examination (Hewlett-Packard Sonos 1000) was carried out with a standardized protocol that included, after a preliminary two-dimensional and color Doppler study, an M-mode echocardiogram for measurement of left ventricular dimensions according to the recommendations of the American Society of Echocardiography.^{6 7 8}

Carotid Ultrasonography
Common carotid wall thickness was measured by B-mode ultrasound with a 7.5-MHz transducer as the distance between the lumen-intima interface and the media-adventitia interface (the so-called intima-media thickness).⁹ The examinations were performed by two sonographers, and videotaped recordings were then examined by independent readers in blind conditions. Four to six measurements were obtained on both sides, and the mean value was calculated.

BP Measurements
BP was measured by sphygmomanometer according to the suggestions of the American Heart Association¹⁰ (clinic BP) and by noninvasive ambulatory monitoring with a SpaceLabs 90207 device. Automatic measurements were performed every 20 minutes during the daytime (7 AM to 11 PM) and every 30 minutes during the nighttime (11 PM to 7 AM), for a total of 64 measurements over a 24-hour period.¹¹

AT₁ A/C¹¹⁶⁶ Genotyping
Genomic DNA was extracted from frozen peripheral blood by standard procedures.

The primers used for polymerase chain reaction amplification of the AT₁ receptor region encompassing the A/C¹¹⁶⁶ polymorphism were those used by Tiret et al.⁵ The amplification mixture was prepared with the GeneAmp reagent kit (Perkin-Elmer Cetus) according to the manufacturer's recommendations, with the addition of 5% dimethyl sulfoxide. After an initial incubation step at 94°C for 3 minutes, the polymerase chain reaction procedure (DNA Thermalcycler 480, Perkin-Elmer Cetus) consisted of 30 cycles of denaturation at 94°C for 30 seconds, annealing at 55°C for 45 seconds, and extension at 72°C for 2 minutes, followed by a final extension at 72°C for 7 minutes. Ten µL of the final amplification product was diluted with 300 µL of 0.4 mol/L sodium hydroxide and blotted onto nylon membranes (Boehringer Mannheim Italia) that were subsequently soaked in 3 mol/L sodium acetate (pH 5.5), exposed on a UV transilluminator for 2 minutes, and then baked at 80°C for 1 hour.

The detection of the A/C¹¹⁶⁶ polymorphism was accomplished by allele-specific oligonucleotide hybridization. The 15-mer probes (AATGAGCATTAGCTA for the A¹¹⁶⁶ allele; AATGAGCCTTAGCTA for the C¹¹⁶⁶ allele) were labeled at their 3' end with digoxigenin-labeled dUTP. The hybridization procedure and immunological detection were performed with a commercially available kit (DIG Nucleic Acid Detection Kit, Boehringer Mannheim Italia) according to the manufacturer's recommendations, with the following specifications: (1) in the prehybridization step, an unlabeled oligo specific for the other allele (allele C if testing allele A, and vice versa) was added, as previously suggested⁵ ; (2) the hybridization temperature was 42°C; and (3) the final washing step (1x SSC, 0.1% sodium dodecyl sulfate) was 2x5 minutes at 42°C (A¹¹⁶⁶) or 46°C (C¹¹⁶⁶). The enzyme-catalyzed color reaction was evaluated by two independent investigators who did not know the corresponding phenotypes. Each sample was run in quadruplicate on separate membranes to allow simultaneous detection of the two alleles in two distinct sessions. In 12 subjects, the assay was technically unsatisfactory in one or both sessions and they were excluded from the analysis; otherwise, there was full agreement between readers and replicates.

Statistical Analysis
Based on previous data obtained in the same population and on reported genotype frequencies,² the power of this study to detect a 10% difference among genotypes, with an value of 0.05, was 99% for BP and approximately 50% for both left ventricular mass and carotid wall thickness.

Analysis of differences in means or proportions between genotypes was conducted by ANOVA and ² statistics (programs 7D and 4F of the BMDP series), respectively; all the inheritance models, ie, recessive (CC vs AC+AA), dominant (CC+AC vs AA), and codominant (CC vs AC vs AA), were considered.

To exclude potential bias, we limited the analysis to only one subject per sibship, randomly chosen, and repeated analysis after exclusion of subjects on chronic drug treatment. In addition, the relationships of the AT₁ A/C¹¹⁶⁶ genotype with the phenotypes of left ventricular mass and common carotid intima-media thickness were reexamined after adjustment for potential confounding variables (age, sex, height, weight, BP, smoking habits, biochemical parameters) considered as covariates (program BMDP-2V).

The probability (P) values for statistical significance are reported without any correction for multiple comparisons.

	Results

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Study Population
The demographic characteristics of the overall sample according to the AT₁ A/C¹¹⁶⁶ genotype are summarized in Table 1. The frequencies of the AT₁ A¹¹⁶⁶ and C¹¹⁶⁶ alleles in the overall sample were 66.5% and 33.5%, respectively. The frequencies of different genotypes (AA=43.8%, AC=45.4%, CC=10.8%) were in agreement with Hardy-Weinberg equilibrium.

View this table: [in this window] [in a new window]   Table 1. Demographic Data and Cardiovascular Risk Factors in the Study Population According to AT1 Receptor A/C1166 Genotype

No significant differences of age, sex distribution, body mass index, and cardiovascular risk factors were observed among genotypes; however, the occurrence of chronic drug treatment was lower in CC homozygotes (P=.057). The frequencies of a positive family history for ischemic heart disease, stroke, dyslipidemia, or diabetes mellitus were not statistically different among AT₁ A/C¹¹⁶⁶ genotypes (Table 2); however, a significantly lower incidence of a positive family history of hypertension was observed in CC homozygotes (P=.027).

View this table: [in this window] [in a new window]   Table 2. Family History of Cardiovascular Disease and Risk Factors According to AT1 Receptor A/C1166 Genotype

Blood Pressure
BP values according to different genotypes are reported in Table 3. In the overall analysis, clinic BP appeared to be associated with the AT₁ A/C¹¹⁶⁶ polymorphism: lower BP levels (a difference of -6.6 mm Hg for mean BP, with a 95% confidence interval of -1.6 to -11.7) were observed in CC homozygotes than in heterozygotes and AA homozygotes, according to a recessive model. This difference was found also in the subgroup of untreated subjects (-5.4 mm Hg, 95% confidence interval of -0.8 to -10.1) but disappeared when ambulatory BP measurements were considered, with differences of -2.4 mm Hg (from +1.7 to -6.6) and +0.7 mm Hg (from +5.3 to -3.9) for daytime and nighttime systolic BP, respectively.

View this table: [in this window] [in a new window]   Table 3. Ambulatory and Casual Blood Pressure in the Study Population According to AT1 Receptor A/C1166 Genotype

When the occurrence of hypertension (clinic BP above 160/95 mm Hg and/or positive clinical history of antihypertensive drug treatment) was considered as a categorical variable (Table 3), a lower frequency of hypertensive subjects was observed in the CC genotype (P=.065).

Left Ventricular Mass and Carotid Artery Wall Thickness
We did not find evidence of an association between the AT₁ A/C¹¹⁶⁶ polymorphism and either left ventricular mass or carotid artery wall thickness (Table 4). This was observed in an overall ANOVA and confirmed after adjustment for covariates. The same conclusion was reached when the analysis was limited to the subgroup of untreated subjects (values in parentheses in Table 4) and by considering as categorical variables the presence/absence of left ventricular hypertrophy, carotid wall thickening, and carotid atheromatous plaques, as defined by currently accepted criteria.¹²

View this table: [in this window] [in a new window]   Table 4. Cardiovascular Structural Phenotypes According to AT1 Receptor A/C1166 Genotype

	Discussion

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The main finding of our study is that in the examined population, AT₁ CC homozygotes present lower BP values, lower prevalence of hypertension (when BP is considered as a dichotomous variable), and less frequent positive family history of hypertension than heterozygotes and AA homozygotes. On the other hand, no evidence of association was detected between cardiovascular structural phenotypes, either left ventricular mass or carotid artery wall thickness, and the AT₁ A/C¹¹⁶⁶ polymorphism.

Association studies are exposed to the risk of bias, but the design of the present study should have avoided several common sources of error. In this respect, its strengths include (1) the selection of a random sample of a general population rather than a case-control design; (2) the adoption of quantitative rather than only dichotomous criteria for both BP and morphological data (with the additional advantage, for BP measurement, of the ambulatory automatic recording technique); and (3) a careful evaluation of any pharmacological treatment potentially interfering with the phenotypes under investigation.

AT₁ A/C¹¹⁶⁶ and BP
We should take into account that the number of variables (ambulatory and clinic BP, daytime and nighttime measurements) and different genetic models examined in this study considerably increases the overall number of comparisons and consequently the chance of an error. We decided to report the raw probability values because in hypothesis-generating studies, such as the present one, an automatic correction for multiple comparisons (Bonferroni's adjustment or one similar) is inappropriate. However, it is evident that the interpretation of positive results in this context must be rather conservative.

In addition, other aspects should be considered in assessing the causal role of the observed association between BP (or family history of hypertension) and the AT₁ A/C¹¹⁶⁶ polymorphism.¹³ Several different considerations weaken the possibility of a true causal relationship. First, the association is no longer present when ambulatory BP is considered. Second, the association between BP and AT₁ A/C¹¹⁶⁶ genotypes is better described by a recessive (CC versus AC plus AA) than by a codominant (CC versus AC versus AA) model of inheritance; thus, a dose-dependent effect is not evident. In addition, since most of the significant differences were found in CC homozygotes, the relatively small number of subjects with this genotype represents an obvious limitation. Finally, there is some inconsistency with previous reports. In fact, Bonnardeaux et al² observed a significant increase of C¹¹⁶⁶ in a group of hypertensive individuals compared with normotensive control subjects, a finding that is the opposite of what we have observed in the present study. On the other hand, no evidence of association between BP and an AT₁ A/C¹¹⁶⁶ gene polymorphism was detected in the population of the ECTIM study⁵ or in a previous group of hypertensive individuals.⁴

Another very important issue is the biological relevance of the AT₁ A/C¹¹⁶⁶ gene polymorphism. The A/C transversion occurs in an untranslated region of the gene and does not characterize per se any functional diversity. Therefore, this polymorphism can be considered exclusively as a possible marker, in linkage disequilibrium with other functionally relevant genetic variants affecting the structure or expression of the AT₁ receptor (or adjacent unknown genes). However, no evidence is available in support of this hypothesis.

AT₁ A/C¹¹⁶⁶ and Left Ventricular Mass
Caution is also needed in interpreting the lack of association with cardiac mass observed in this study because the number of subjects under investigation was probably not sufficient for the confident exclusion of the possibility of a ß-type error. In fact, the 95% confidence interval of the difference observed between CC subjects and the other two genotypes (from -31.9 to 21.9 g) is compatible with potential "real" differences of clinical relevance. To the best of our knowledge, this is the first report investigating the relationship between AT₁ gene polymorphism and cardiac mass. Therefore, in view of the potential relevance of this gene in the modulation of cardiac growth, further studies with more statistical power may be justified to address this question.

AT₁ A/C¹¹⁶⁶ and Carotid Wall Thickness
The potential influence of the renin-angiotensin system on the development of arterial wall thickening has been proposed.¹⁴ In a smaller sample of the same general population, we previously found an association between the angiotensin-converting enzyme insertion/deletion polymorphism and the common carotid intima-media thickness.¹⁵ In the present study, the observed differences among AT₁ A/C¹¹⁶⁶ genotypes seem to exclude the possibility that "real" differences of clinical importance may exist. It has been previously reported that the CC genotype may be associated with increased aortic stiffness, as evaluated by measurement of carotid-femoral pulse-wave velocity, in hypertensive subjects.⁴ With the obvious limitations caused by the different approach used in the study of Benetos et al⁴ and the present study (hypertensive subjects recruited from an outpatient clinic versus the general population; aorta versus common carotid artery), it appears that vascular structural alterations cannot account for the observed association of aortic stiffness with the AT₁ A/C¹¹⁶⁶ polymorphism. This is in keeping with previous findings (see Laurent¹⁶ for review) suggesting that arterial wall hypertrophy may not necessarily be associated with reduced arterial distensibility.

In conclusion, the AT₁ A/C¹¹⁶⁶ gene polymorphism is possibly associated with arterial BP but does not show any relationship with cardiac and vascular structure. Our study does not support a major role of this gene polymorphism as a marker of cardiovascular phenotypes associated with increased cardiovascular risk.

	Acknowledgments

 
This study was supported in part by grants from Regione Lombardia (Settore Sanita ed Igiene) and from the Italian National Research Council (CNR 60%).

Received March 29, 1996; first decision May 7, 1996; accepted July 2, 1996.

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