(Hypertension. 1999;34:1097-1100.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Genetic Polymorphisms of the Renin-Angiotensin System and Atheromatous Renal Artery Stenosis
From the Department of Clinical and Experimental Medicine, Chair of Internal Medicine (O.O., S.G., S.F., D.G., C.R., R.C.), Institute of Biology and Genetics (E.T., C.S., P.F.P.), and Institute of Radiology (G.M.), University of Verona, Verona, Italy.
Correspondence to Oliviero Olivieri, Department of Clinical and Experimental Medicine, Cattedra di Medicina Interna, Università di Verona, Policlinico Borgo Roma, 37134 Verona, Italy. E-mail olivieri{at}cmib.univr.it
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Abstract |
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Abstract—Genes that influence the renin-angiotensin system have been investigated in recent years as potential etiologic candidates of cardiovascular and renal diseases. In atheromatous renal artery stenosis (RAS), a condition characterized by persistent activation of the renin-angiotensin system, the study of these genes may be of particular relevance. We evaluated angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T, and angiotensin II receptor (ATR) A1166C polymorphisms in relation to the occurrence of RAS. We studied 58 patients with angiographically documented RAS; 102 normotensive subjects with normal coronary arteries and no history or clinical or instrumental evidence of atherosclerosis in other vascular districts were considered the control group. Patients had a significantly higher D allele frequency (0.70 versus 0.55;
2 6.88,
P=0.01; odds ratio [OR] 1.9, 95% CI 1.17 to 3.07)
than did the control population; 48.3% of patients were homozygous for
DD (2 6.62, P<0.05; OR 2.04, 95% CI
1.05 to 3.95); and only 8.6% carried the II genotype (OR 0.34,
95% CI 0.19 to 1.47). No significant association was found for AGT
M235T and ATR A1166C. Our results suggest a predisposing role for ACE
genetic polymorphism in the development and progression of
atheromatous RAS.
Key Words: renal artery • angiotensin-converting enzyme • angiotensinogen • angiotensin II receptor • polymorphism
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Introduction |
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Atheromatous renal artery stenosis (RAS) is generally considered a localization of a more generalized vascular disease.1 2 3 The estimated prevalence of RAS varies according to the various studies and the clinical features of the patients, ranging from 1% to 2% in the overall hypertensive population to 30% to 40% in selected hypertensive patients with overt atherosclerotic disease (14% to 38% in patients with aorto-occlusive or peripheral vascular disease and 11% to 30% in patients with coronary artery disease) (for a recent review, see Reference 44 ). In contrast, very low prevalences (<1%) are reported in hypertensive patients without clinical evidence of vascular disease.1 5 6 7 8 9
Unlike the acquired vascular risk factors that have frequently been associated with this condition,1 5 6 7 8 9 the role of genetic predisposition to RAS has been studied inadequately. The only report published on the topic to date demonstrated an increased frequency of deletion polymorphism of the angiotensin 1–converting enzyme (ACE) in RAS patients compared with controls.10
ACE and angiotensinogen (AGT) display a genetic
polymorphism in their circulatory or cellular
levels,11 12 13 which may provide the basis for a relation
between the constitutive activity of the renin-angiotensin
system and the development of vascular damage in individual subjects.
Plasma and cellular ACE levels are stable within individuals but show
marked interindividual variability; 
50% of this variability is
accounted for by a major gene effect.11 12 An
insertion/deletion (I/D) polymorphism of a 287-bp sequence near the
3' end of intron 16 of the ACE gene appears to be responsible for this
variability.14 Specifically, it has been demonstrated that
the presence of the D allele correlates with higher plasma and
cellular ACE levels compared with the levels observed in subjects
carrying the I allele, with the result that different ACE
polymorphisms have graduated effects on phenotypical ACE expression
(DD>ID>II).
Plasma AGT concentrations are also related to a polymorphic variant of the corresponding gene, the M235T mutation, with individuals homozygous for the T allele having the highest and individuals homozygous for the M allele having the lowest plasma AGT levels.13
Polymorphisms have also been described in the gene encoding subtype 1 of the angiotensin II receptor (ATR), but these mutations have not yet been linked to any biological phenotype.15 Nonetheless, it has been postulated that the A1166C polymorphism of the ATR gene may potentiate the cardiovascular risk carried by the ACE D allele and contribute to aortic stiffness in hypertensive patients.16 17
In the present study, we evaluated the renin-angiotensin system ACE I/D, AGT M235T, and ATR A1166C polymorphisms in relation to the occurrence of RAS.
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Methods |
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We studied 58 consecutive patients referred to our Hypertension Clinic from May 1996 to September 1998 and diagnosed as having RAS. All but 2 patients having a significant RAS (at least 70% lumen reduction) were enrolled; the 2 remaining patients refused to give blood for DNA evaluation. Patients referred to our Hypertension Clinic ranged from 250 to 300 patients per year, and RAS patients represented 10% to 12% of the total. Patients with renal artery lumen narrowing <70% were excluded in order to compare only phenotypically extreme conditions.
All the patients included in the present study underwent angiographic evaluation and were found to have significant monolateral or bilateral RAS (at least 70% lumen reduction). All of them were examined for severe hypertension requiring >2 drugs and/or associated with clinically evident vascular disease, mainly affecting the lower extremities. Angiographic study was performed when a moderate or high index of clinical suspicion, defined according to Mann and Pickering,6 was recognized.
Routine biochemical and clinical data were collected on the occasion of the first examination, venous blood samples for genetic analysis were taken after renal angiography, and the patient’s informed consent was obtained.
Because renal angiography was regarded as unacceptable in control subjects for ethical reasons, we exploited the possibility offered by our recently performed large case-control study in subjects with an angiographically documented normal or pathological coronary bed.18 One hundred two subjects with valvular heart disease and normal coronary arteries who proved normotensive at 3 consecutive evaluations over a 3-month period were considered as a control group. Hypertension was defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >95 mm Hg. Moreover, control subjects were enrolled providing that they had both a normal coronary angiogram at cardiac catheterization and no history or clinical or instrumental evidence of atherosclerosis in vascular districts other than the coronary bed. With these selection methods, the prevalence of renal artery disease can be considered extremely low or close to zero.1 5 6 7 8 9
Mutation Analysis
Mutation analysis (as well as routine biochemical
analysis) was conducted as a study that was blinded as to
whether the sample came from an RAS or a control subject. Genomic DNA
was extracted from whole blood by use of standard methods.
To determine the ACE genotype, genomic DNA was amplified by polymerase chain reaction (PCR) with the hace3 primer pair as described by Lindpaintner et al.19 Each sample with the DD genotype was subjected to a second independent PCR amplification with the hace5 primer pair that recognized only the I allele as described by Shanmugam et al.20
Analysis of M235T polymorphism in the human AGT gene was performed by PCR and Tth 111 I restriction, as described by Russ et al.21 A1166C polymorphism of the ATR gene was detected by PCR and DdeI digestion, as reported by Katsuya et al.22
Statistical Analysis
Statistical analysis was performed by the Systat 5.2.1
package working on a Macintosh Performa 5300. Quantitative data were
analyzed with the Student t test or ANOVA with the
Tukey post hoc comparison of the means when appropriate. Qualitative
data were analyzed by 2 test. A value
of P<0.05 was considered significant.
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Results |
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The relevant characteristics of the population studied are summarized in Table 1. As expected, the RAS patients presented more conventional cardiovascular risk factors (higher levels of glucose, triglycerides, and LDL cholesterol and lower HDL cholesterol levels) and higher (although not yet statistically significant) serum creatinine levels than did the control subjects.
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The distribution of the genotypes for the 3 polymorphisms
in the control population was compatible with a Hardy-Weinberg
equilibrium. Table 2 indicates the
allele frequencies and genotype distributions in RAS
patients and control subjects. The allele frequencies of AGT M235T
and the ATR A1166C polymorphisms were not statistically different
between patients and controls. The frequency of the D allele in the
RAS group was significantly higher than that in the control group (0.70
versus 0.55; 2 6.88, P=0.01; odds
ratio [OR] 1.9, 95% CI 1.17 to 3.07). An increased frequency of the
DD genotype was also evident (DD 28 of 58 patients in the RAS
group versus 32 of 102 subjects in the control group;
2 6.62, P<0.05; OR 2.04, 95% CI
1.05 to 3.95). The II genotype was associated with a lower
relative risk of RAS (OR 0.34, 95% CI 0.19 to 1.47). There was no
preferential association between ACE and AGT or ATR genotypes
in the patients (Table 3).
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The distribution of the main vascular risk factors (smoking and levels of total, LDL, and HDL cholesterol, triglycerides, uric acid, and glucose) and serum creatinine levels were unaffected by I/D polymorphism (data not shown).
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Discussion |
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The main result of the present study was the demonstration that patients affected by atheromatous RAS had a significantly higher D allele frequency than did the control population; about half of them were DD homozygotes and only 8.6% were II homozygotes compared with 31% and 22% in the control population, respectively (Tables 2 and 3). In contrast, AGT and ATR polymorphism alleles and genotypes were similarly distributed between the 2 populations and were not associated with the occurrence of renal vascular pathology (Table 2).
Despite the current interest in the genetics of the renin-angiotensin system in relation to the vascular and renal risk profile, RAS, a clinical condition characterized by persistent activation of this system,23 24 25 26 has not been extensively studied. Because of the relative scarcity of reports, comparison of our results with previously published data are objectively limited. To the best of our knowledge, the only article on this topic is the study by Missouris et al,10 who evaluated ACE polymorphism in 56 English RAS patients; AGT and ATR polymorphisms were not analyzed. Besides the geographical origin, a relevant difference vis-à-vis the present study was that Missouris et al used subjects from the general population as a control group, without any objective angiographic information about their coronary arteries. With our approach, however, we were able to rule out the possibility that the controls might have had substantial (though not clinically manifest) coronary atherosclerosis; thus, the occurrence of atheromatous RAS would also be highly unlikely.1 5 6 7 8 9 Having considered objective conditions, we therefore feel confident that we reduced the likelihood of spurious results. Apart from this difference, however, the D allele frequency observed in the English population was similar to that found in our Italian patients.
Reported frequencies of the DD genotype in "control"
populations vary from 16% to 28% in Japanese
subjects27 28 to 22% to 32% in
Caucasians.19 27 28 29 30 Our data confirm that the range of
frequency of DD polymorphism in Northern Italy is of the same order
of magnitude as that generally reported for Caucasian populations
(homozygosity in our control subjects was 31.37%). At this level, any
possible selection bias deriving from a "spurious" low frequency in
the control population and leading to an erroneous statistical
difference in favor of the RAS group should be excluded. In addition,
the distribution of the ACE genotypes in the control population
was compatible with a Hardy-Weinberg equilibrium.
Another possible source of bias lies in the power of the study. The present study analyzing 320 alleles had a predicted 80% power (5% probability) of detecting an allelic difference such as that observed in D allele frequency between the RAS and control groups (Table 2); thus, the results should be reliable.
The problem of the power of the study is also of major relevance with regard to the negative results that we observed for AGT and ATR polymorphisms. For this reason, our findings do not allow us to completely rule out an association between AGT and ATR polymorphisms and RAS risk; therefore, firm conclusions should be avoided. However, it should be borne in mind that the allele frequency of AGT was so balanced in the 2 groups (Table 2) that a positive association with this polymorphism appears highly improbable.
The predisposing role of ACE I/D polymorphism in cardiovascular disease has been a subject of controversy and debate in recent years: both positive and negative associations with coronary atherosclerotic disease (CAD) and myocardial infarction (MI) have been reported (for review see References 27, 28, 31, and 3227 28 31 32 ). Controversial findings have also been reported for several other pathological conditions such as cerebrovascular disease (for a review see Reference 3333 ), left ventricular hypertrophy,34 35 36 and diabetic or nondiabetic nephropathy (for review see References 37 and 3837 38 ). Note that very few of the numerous published studies reported an elevated DD genotype frequency such as that found in the present study. If we also take into account the results reported by Missouris et al,10 an estimated frequency of DD in RAS patients should range from 41% to 48.3% (mean 44.7%, 51 of 114 patients), and the estimated D allele frequency should range from 0.64 to 0.70 (mean 0.67).
As already stated, unsuspected RAS is commonly found in patients
with angiographically documented CAD, with a prevalence ranging from
11% to 30% (the mean for 11 published reports was
23%).4 If 50% of patients affected by RAS carry a DD
genotype, then 5.5% to 15% (mean 11.5%) of DD
genotypes observed in a population of CAD patients may vary in
relation to the relative proportion of unsuspected RAS patients
included in the study. Because patients affected by CAD or MI were not
angiographically checked for RAS in the previous studies, negative or
positive statistical associations with I/D polymorphism might
depend on this unrecognized confounding factor. Similarly, one can
speculate regarding the reported increase in D allele frequency in
cerebrovascular disease or myocardial hypertrophy, which
commonly complicate the clinical history of the patients with
RAS.2 39
In conclusion, several lines of evidence suggest a close link between ACE polymorphism, activation of the renin-angiotensin system, and the causes of RAS. Reported controversial associations between D allele frequency and various forms of cardiovascular pathology (eg, coronary artery disease) should be reconsidered in light of this potentially confounding factor.
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Acknowledgments |
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This study has been supported by grants from the Ministry of the University and Scientific and Technological Research, the Veneto Region Department of Health, the Fondazione Cariverona-Progetto Sanità 1996–97, and CNR Target Project Biotechnology.
Received April 16, 1999; first decision May 14, 1999; accepted June 28, 1999.
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