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(Circulation. 1995;91:2721-2724.)
© 1995 American Heart Association, Inc.

Articles

Angiotensin-Converting Enzyme I/D Polymorphism and Arterial Wall Thickness in a General Population

The Vobarno Study

Maurizio Castellano, MD; Maria Lorenza Muiesan, MD; Damiano Rizzoni, MD; Marina Beschi, MD; Gianfranco Pasini, MD; Angelo Cinelli, MD; Massimo Salvetti, MD; Enzo Porteri, MD; Giorgio Bettoni, MD; Reinhold Kreutz, MD; Klaus Lindpaintner, MD; Enrico Agabiti Rosei, MD

From Semeiotica Medica, Center of Hypertension and Cardiorespiratory Risk Factors, University of Brescia and I Divisione Medicina Generale, Spedali Civili di Brescia (M.C., M.L.M., D.R., M.B., A.C., M.S., E.P., G.B., E.A.R.); the Divisione Medicina Generale, Ospedale di Gavardo (G.P.); and Brigham and Women's Hospital, Boston, Mass (R.K., K.L.).

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

	Abstract

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Background It has been reported that the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin I–converting enzyme (ACE) gene is associated with conditions of increased cardiovascular risk, including left ventricular hypertrophy.

Methods and Results Considering that a genetically determined overactivity of the renin-angiotensin system may influence cardiac as well as vascular growth, we investigated possible relations between ACE I/D genotype and carotid artery wall thickness (B-mode ultrasound) in 199 subjects, 50 to 64 years old, sampled from the general population of Vobarno, a small town in northern Italy. ACE DD genotype was associated with significantly higher common carotid artery intima-media thickness (P=.003). The occurrence of carotid atherosclerotic plaques was similar in the different genotypes. There was no association of the ACE I/D genotype with blood pressure values (either casual or 24-hour ambulatory monitored).

Conclusions ACE DD genotype may be considered a risk factor for the development of common carotid intima-media thickening in our study population.

Key Words: angiotensin • enzymes • arteries • population • genes

	Introduction

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After the detection of an insertion/deletion (I/D) polymorphism in intron 16 of the gene encoding angiotensin-converting enzyme (ACE),¹ a growing number of reports have described associations or, less frequently, lack of association between ACE I/D genotypes and cardiovascular or noncardiovascular diseases.

An association with ischemic heart disease was found in the ECTIM study, which showed that the DD genotype is more frequent in patients with recent myocardial infarction² and in subjects with a parental history of fatal myocardial infarction.³ This observation has been supported by other studies and extended to different pathological conditions.^{4 5 6 7 8 9} On the other hand, there are also contrasting results^{10 11 12} ; therefore, a conclusive agreement about the role of ACE genotype in the genetics of cardiovascular disease is still far from being reached.

Through its role in the conversion of angiotensin I to angiotensin II and in the inactivation of kinins, ACE may modulate cardiovascular growth.¹³ This is the rationale underlying the recently reported association of DD genotype with the presence of left ventricular hypertrophy, as defined by ECG criteria¹⁴ or echocardiography¹⁵ ; furthermore, DD genotype frequency has been found to be increased in patients with hypertrophic cardiomyopathy.¹⁰

An association between increased intima-media thickness of common carotid arteries and higher plasma ACE activity has recently been described.¹⁶ In this study, we investigated the possible relation of ACE I/D genotype with carotid wall thickness in a sample of a general population. Subjects were recruited from a cross-sectional study designed to investigate the prevalence of cardiovascular structural alterations in the middle-aged general population of Vobarno, a small town of northern Italy.

	Methods

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Subjects
Subjects were randomly selected from the 50- to 64-year-old segment of the Vobarno population. Three hundred sixty-nine subjects (two thirds of the eligible population) were asked to participate: phenotypic data and DNA were obtained in 199 individuals, who are the subjects of the present study. Since there were a few siblings (8%) in our population, to avoid possible bias we randomly chose only one member per family, reducing the overall number of individuals used for all data and analyses to 189. All subjects gave informed consent, and the procedures were performed at the Department of Medical Sciences, Chair of Semeiotica Medica, of the University and the Spedali Civili of Brescia. Medical histories were collected for all subjects, with particular emphasis on cardiovascular and metabolic diseases, smoking habits, and chronic drug treatment. Forty-four subjects were treated for hypertension (n=30), ischemic heart disease (n=5), hyperlipidemia (n=4), or combinations thereof (n=5).

After overnight fasting, blood samples were taken for serum glucose, total cholesterol, triglycerides, and uric acid measurement, as well as for genomic DNA extraction.

Blood pressure was evaluated by measuring casual blood pressure in standardized conditions and by noninvasive 24-hour ambulatory blood pressure monitoring (Spacelab Inc), with measurements every 20 minutes during the day (7 AM to 11 PM) and every 30 minutes during the night.

B-Mode Ultrasound
B-mode ultrasound (Hewlett Packard Sonos 1000) was used to directly image arterial walls of the extracranial carotid arteries. Investigations were performed by two trained sonographers, and videotape recordings were subsequently examined by two independent readers using measure-morphometric software implemented in the echocardiograph. The distance between the lumen-intima interface and the media-adventitia interface, which represents the so-called "intima-media thickness" (IMT), was measured in the common carotid, the carotid bifurcation, and the origin of internal carotid of both sides. Several measures (6 to 12) were obtained in each arterial segment according to a previously described protocol,¹⁷ and the mean value of all measurements on both sides was calculated. Mean absolute difference ±SD between replicate scans of the common carotid was measured in a subgroup of 20 subjects, resulting in 0.05±0.04 and 0.06±0.03 mm for intraobserver and interobserver comparisons, respectively.

Detection of ACE I/D Polymorphism
Genomic DNA was extracted from peripheral blood samples by standard techniques. The polymerase chain reaction was optimized to avoid mistyping of ID heterozygotes^{18 19} ; we used a set of primers (sense, 5'-GCCCTGCAGGTGTCTGCAGCATGT-3'; antisense, 5'-GGATGGCTCTCCCCGC CTTGTCTC-3') that have a higher GC content and lower free energy at the 3' end, compared with previously published primers,¹ and used dimethyl sulfoxide 5% in the amplification mixture. The amplified products (319 bp and 597 bp for D and I alleles, respectively) were fractionated on 1.5% agarose gel and visualized by ethidium bromide staining. We did not notice any ambiguous readings, and a second amplification of a random subset of DD genotypes with an insertion-specific antisense primer¹⁸ always showed consistent results.

Statistical Analysis
Statistical analysis of differences in means or proportions between ACE genotypes was performed with ANOVA and ² statistics, respectively. In addition, the association of ACE genotype with carotid thickness was investigated by means of logistic regression analysis,²⁰ taking into account potential confounding variables such as age, sex, blood pressure, body mass index, smoking habits, serum glucose, total cholesterol, triglycerides, and uric acid; we also considered any chronic cardiovascular or hypolipidemic drug therapy as potentially interfering and repeated the analyses after exclusion of treated subjects. We examined our data according to a recessive (DD versus DI/II), codominant (DD versus DI versus II), or dominant (DD/DI versus II) genetic model.

	Results

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In the 189 subjects, allele frequency was 64% for allele D and 36% for allele I. The overall genotype distribution (DD, 40%; ID, 48%; II, 12%) was consistent with Hardy-Weinberg equilibrium; the frequency of allele D was slightly higher than those reported by other investigators but was within the 95% CI (42% to 66%) calculated from a series of 14 published reports; this difference may be due to the relative genetic isolation of the population studied or may reflect a possible sampling bias due to the relatively small number of probands studied, but it does not affect the validity of comparing quantitative, raw morphometric data within the population across the genotypes.

No significant differences between genotypes were found with respect to sex, age, body mass index, casual and 24-hour monitored blood pressures, serum glucose, total cholesterol, triglycerides, or uric acid (Table 1).

View this table: [in this window] [in a new window]   Table 1. Demographic, Hemodynamic, and Humoral Data in the Vobarno Study Population

Carotid wall thicknesses were not significantly different among ACE ID genotypes in an overall analysis. Common carotid artery mean IMT of DD subjects was slightly higher compared with DI/II, but the difference was of borderline statistical significance (P=.058) in a multivariate analysis. However, common carotid artery mean IMT was significantly higher in DD subjects (Table 2) in a multivariate analysis of subjects without chronic drug treatment (DD versus DI/II, P=.003). In these subjects, there was also a trend toward a dominant effect (DD/DI versus II) in carotid bifurcation and internal carotid IMTs, but the differences were not statistically significant after correction for confounding variables.

View this table: [in this window] [in a new window]   Table 2. Carotid Intima-Media Thickness in Untreated Subjects

Several different criteria have been used to define the dichotomous variable presence/absence of atheromatous plaques in the carotid district. In this study, we considered three different criteria: (1) IMT 1.3 mm,¹⁷ (2) IMT 1.5 mm,²¹ and (3) distinct areas where IMT was more than 50% greater than adjacent sites.²² Regardless of the definition criterion used, no association of ACE genotype with the occurrence of atherosclerotic plaques in the examined carotid segments was found (Table 3).

View this table: [in this window] [in a new window]   Table 3. Presence of Atheromatous Plaques According to Different Proposed Criteria

	Discussion

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In this cross-sectional population study, we found an increased thickness of carotid artery intima-media layer in the ACE DD genotype. The association was observed only in subjects who did not take chronic drug therapy, and this may be explained by the relatively greater number of treated hypertensive patients with the II genotype. Furthermore, it was statistically significant only in the common carotid segment; in this respect, it is conceivable that different artery segments are more or less affected by a pathological process, but it should also be considered that the common carotid artery is most reliably visualized²³ ; the smaller dispersion (SEM) for common carotid mean IMT is compatible with both explanations. Although the degree of statistical significance is quite high and is present even after Bonferroni's adjustment for multiple testing, it is still difficult to assess the potential pathophysiological relevance of a 12% average increase of IMT in the DD genotype. Carotid wall thickening has been related to enhanced levels of cardiovascular risk factors and to an increased risk of myocardial infarction.²⁴ It may reflect an early phase of the atherosclerotic process or, alternatively, a substantially different underlying disorder not necessarily related to hyperlipidemia and atherosclerosis. The absence of association with the occurrence of atherosclerotic plaques would be in favor of the second hypothesis, but our study may not have sufficient statistical power to detect such an association.

Vascular thickening may be influenced by a genetically determined overactivity of circulating or autocrine/paracrine renin-angiotensin systems.²⁵ This aspect has not been investigated, but our finding could be regarded as the genotypic counterpart of the previously observed association of higher plasma ACE activity with common carotid wall thickening.¹⁶ It has been reported that the D allele is associated with increased circulating ACE activity,¹ suggesting that the I/D region may be linked to sequences of the ACE gene that control its transcription or the bioactivity of the enzyme; the key role of ACE in the formation of angiotensin II and inactivation of kinins would represent the final link to vascular growth.¹³ Alternatively, ACE ID polymorphism may be linked to a close, unidentified gene that plays a role in vascular growth regulation.

In conclusion, we observed a statistically significant increase of common carotid IMT in the DD subjects, whose consistency in different populations and pathophysiological relevance still need to be assessed by larger and prospective association studies or linkage-based family studies.

	Acknowledgments

 
This study was supported in part by grants from the Ministero della Università e della Ricerca Scientifica e Tecnologica (60%, 1992-1993) and from Regione Lombardia. We thank the Amministrazione Comunale of Vobarno (Andrea Barbiani) for valuable assistance and Alessandra Panarotto for valuable technical help.

Received March 8, 1995; revision received March 27, 1995; accepted April 3, 1995.

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