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(Circulation. 1996;94:236-239.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin-Converting Enzyme Gene Polymorphism

What to Do About All the Confusion?

Donald R.J. Singer, MD, MRCP; Constantinos G. Missouris, MRCP; Steve Jeffery, PhD

the Clinical Pharmacology Unit, Department of Pharmacology and Clinical Pharmacology (D.R.J.S.), Blood Pressure Unit (C.G.M.), and Department of Medical Genetics (S.J.), St George's Hospital Medical School, London, England.

Correspondence to Dr D.R.J. Singer, Clinical Pharmacology Unit, Department of Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE England. E-mail d.singer@sghms.ac.uk.

Key Words: genetics • Editorials • angiotensin • cardiovascular diseases

	Introduction

Top Introduction References

 
There is great continuing interest in the link between a deletion variant of the gene for ACE and increased incidence of MI.¹ Although some studies^{2 3 4 5} have failed to confirm this finding, many^{6 7 8 9 10} have reported an association between the ACE*D allele and CHD, including several recent articles published in Circulation. Other positive associations with the ACE*D allele include restenosis after coronary angioplasty,⁶ cardiac hypertrophy and remodeling,^{11 12 13} ischemic or idiopathic dilated cardiomyopathy,¹⁴ hypertrophic cardiomyopathy,¹⁵ atheromatous renal artery stenosis,¹⁶ lacunar stroke,¹⁷ and diabetic nephropathy.¹⁸

Controversy Regarding ACE*D and Ischemic Heart Disease
The alu repeat is the most common family of repeats in the human genome. The insertion that gives rise to the ACE*I allele is an alu repeat in intron 16 of the ACE gene.¹⁹ The ACE*D allele results from the absence of the above insertion in the ACE gene. There is major disagreement about which individuals with the ACE*D allele are at greater risk of cardiovascular disease. The finding by Cambien et al¹ that classically low-risk individuals (low body mass index and low apolipoprotein B) are more likely to develop MI was not confirmed by Ludwig and colleagues⁸ or Mattu and colleagues.⁹ Although Mattu et al⁹ reported an association of the ACE*D allele with CHD in low-risk patients, this association was lost when the data were corrected for body mass index. Ludwig et al⁸ showed no such correlation but found that the ACE*D allele predicts MI. However, their sample size was only adequate to detect an odds ratio of >3.2 for an association between the ACE*D allele and CAD in low-risk patients.⁸ In fact, the frequencies of ACE*D in patients with CAD, CAD/MI, and low-risk CAD/MI were 0.53, 0.59, and 0.64, respectively, a trend that fits with the low-risk hypothesis.⁸ These differences between the studies may be explained in part by differences in the sensitivity of the methods used to assess for CHD. Mattu et al⁹ used the Rose questionnaire and ECGs for diagnosis, whereas Ludwig et al⁸ used coronary angiography.

In contrast to these four large studies, Katsuya et al⁵ reported no increase in risk associated with ACE*D/D but found a twofold increase in risk of CHD associated with the angiotensinogen T235 polymorphism in a cross-sectional case-control study of 422 survivors of angina or MI. Most recently, a study performed in Germany¹⁰ in 920 white males in whom coronary arteriograms were performed has supported the findings of Cambien et al¹ of a significant association between ACE*D/D genotype and ischemic heart disease in low-risk subjects. Dilated cardiomyopathy was excluded because of its association with increased ACE*D/D frequency, which may explain in part why ACE genotype was not associated with CAD or with MI in the group as a whole.¹⁰ However, the ACE*D/D genotype was more common in subjects with MI who were considered to be at reduced risk on the basis of lower body mass index and cigarette consumption, and it was more common in subjects with CAD and low cholesterol and triglyceride levels.¹⁰

In their large, prospective study, Lindpaintner et al³ also failed to find the expected association between ACE*I/D alleles and MI. Therefore, it is important to consider whether type III error may have occurred in previous positive studies. There have been striking differences in DD genotype frequency between studies. In some studies, the ACE*D/D genotype frequency was lower than expected in control subjects. In other studies, the ACE*I/D allele frequencies were not in Hardy-Weinberg equilibrium, which indicates possible selection bias. This could lead to a false impression of increased ACE*D/D frequency in patient groups.

An alternative explanation is that the presumably more heterogeneous genetic background of Lindpaintner's North American population compared with the European study populations resulted in loss of linkage disequilibrium between the ACE*D/I markers and another disease mutation and therefore led to the negative results.⁴ However, several positive studies have also been conducted in North America.^{8 14} The study by Lindpaintner et al³ may also have been confounded by bias in the selective use of ACE inhibitors or aspirin in ACE*D/D patients and by the fact that the subjects were older than in some previous positive studies, and therefore environmental factors may have masked genetic mechanisms marked by the presence of the ACE*D allele. An additional concern about these results is that the population under study was a highly selected group, US physicians. Results on mortality were not reported in the New England Journal of Medicine article³ despite the fact that access to information on deceased individuals is a major advantage of a prospective design versus a case-control design for the study of genetic risk factors. Previous publications of the Physician's Health Study indicated that CHD mortality in that cohort was 15% of that expected.

A further explanation is possible selection bias in the earlier reports of association between the D allele and MI. In these initial studies, samples for genetic studies were collected some months after clinical diagnosis of MI¹ ; thus, only late survivors were included. This raises the obvious question, is the D allele or the absence of the I allele a marker of improved survival? Circumstantial evidence is provided by the fact that French centenarians have a high ACE*D allele frequency.²⁰ However, Evans et al²¹ reported that there is a similar increase in ACE*D allele frequency in autopsy studies of patients with MI compared with earlier studies confined to survivors with CAD. Second, Katsuya et al,⁵ unlike Cambien et al,¹ found no significant correlation between ACE*D/D and diagnosis of CAD in patients who survived beyond discharge from the hospital. Thus, a survival benefit associated with the ACE*D allele seems unlikely to explain the many reports of positive associations between the ACE*D allele and cardiovascular disease. Indeed, there is evidence from an Australian study²² that reported a reduced frequency of the D allele in subjects at increased familial risk of CHD that indicates that the ACE*D allele may be a marker of adverse prognosis. This latter finding, however, may have been confounded in part because these patients also had hypertension, an independent risk factor for CHD.

An important methodological issue is that ACE*I/D may be mistyped as ACE*D/D.²³ To lead to systematic observations of higher ACE*D/D frequency in disease groups, this mistyping would need to occur more commonly in patients than in control subjects. This mistyping problem has been estimated at 5% of DD alleles identified by older methods and is thus unlikely to be a major explanation for the large number of positive studies reported. Furthermore, several positive reports^{16 21} have used insertion-specific primers to avoid D/D mistyping.

ACE*D Allele and Coronary Restenosis
In a recent large study, Samani et al²⁴ found no significant link between the ACE*D allele and coronary restenosis after angioplasty, in contrast to an earlier study by Ohishi et al.⁶ The main aim of the study by Samani et al was to assess anticoagulation for prevention of restenosis, and ACE*I/D alleles were not factors in treatment randomization. Thus, there may have been inadvertent bias in drug therapy or response.²⁴ However, despite a lack of correlation with severity of CAD preangioplasty or with restenosis rate, the ACE*D allele was linked to unstable angina and the need for urgent angioplasty.²⁴

This post hoc analysis must be interpreted with caution. However, taken together, these observations^{8 24} suggest an intriguing link between the ACE*D allele and some aspect of the process that leads to plaque instability and not just with atheroma or its stable progression. This suggestion is supported by the recent finding in stroke patients of a positive association of the D allele or DD genotype with risk of lacunar infarction but not with carotid atheroma.¹⁷

Mechanisms for the Association Between the ACE*D Allele and Disease
The increased risk of MI associated with the ACE*D allele is graded, with low risk for ACE*I/I, intermediate risk for ACE*I/D, and high risk for ACE*D/D genotypes, which suggests codominant inheritance.¹ The mechanisms underlying positive associations between the ACE*I/D alleles and disease are not yet clear. Any explanation must take into account that the effect appears to be independent of blood pressure, because all studies but one²⁵ have failed to show any association between the ACE gene locus and hypertension. However, there is increasing evidence to link the renin-angiotensin-aldosterone system to regulation of cardiac and vascular growth and thus to cardiac hypertrophy and atheroma.

ACE circulates in plasma and is present on the surface of endothelial cells, where it stimulates conversion of inactive Ang I to the highly active octapeptide Ang II. Ang II is a potent vasoconstrictor and may also increase vascular smooth muscle growth, particularly after endothelial injury.^{26 27 28} Inhibitors of ACE prevent myointimal proliferation after vascular injury.²⁹ ACE also inactivates bradykinin; hence, ACE inhibitors both decrease Ang II levels and increase levels of bradykinin. Bradykinin is a vasodilator that inhibits vascular smooth muscle cell proliferation and can stimulate the release of endothelial vasodilators, including nitric oxide and prostacyclin.^{30 31} Treatment of hypertension with ACE inhibitors leads to greater regression of left ventricular hypertrophy than is attributable to the fall in blood pressure alone.³²

Levels of tissue³³ and circulating ACE activity are under tight genetic control.³⁴ Circulating ACE activity is higher in the presence of the ACE gene deletion polymorphism,^{16 35 36 37 38} even in patients with CAD.^{16 36 37} A study of left ventricular samples from organ donors without cardiac disease, reported at the 68th Scientific Sessions of the American Heart Association, showed that local cardiac ACE activity also increased in the presence of the ACE*D allele.³³

There appears to be an interaction between alleles of the Ang II type 1 receptor (AGT1R) gene and increased risk of MI, with a stronger association in patients with both ACE*D/D and the AGT1R*C allele.³⁹ Taken together, the above observations support the attractive hypothesis that effects of the ACE*I/D allele polymorphism on cardiovascular disease are mediated by altered expression of tissue and/or circulating ACE. However, the finding by Gardemann et al¹⁰ of an association between CAD and ACE*D/D genotype but not circulating ACE activity in low-risk subjects suggests that non–ACE-mediated effects are also important in some patients.¹⁰

Need for Further Studies
Further studies are needed to shed more light on the significance of positive associations between ACE*D alleles and disease. Genetic and biochemical mechanisms for disease causation need to be unraveled. Clues may come from genetic studies in black versus white populations, because there are marked differences in the prevalence of cardiovascular disease and in the frequency of the ACE*D allele both between black populations and in black compared with white populations.^{40 41} Furthermore, although circulating ACE activity is under tight genetic control, the degree to which this is linked to the ACE*I/D polymorphism shows marked genetic differences.^{10 38}

The fact that the alu repeat that gives rise to the I allele is within an intron makes it highly improbable that it could exercise any direct regulatory function on the ACE gene. This being the case, one major area of further research in the molecular field should be analysis of the promoter region of the gene to look for any mutations that might be linked to the D allele.

Tiret et al,³⁴ using segregation and linkage analysis, suggested that the ACE*I/D polymorphism, which accounted for 28% of the total variance of plasma ACE in their Caucasian subjects, is a marker in strong linkage disequilibrium with a functional variant (S/s) in the ACE gene. In their analysis, this major gene effect accounted for 44% of interindividual variability in circulating ACE levels.³⁴ In contrast, a study in black Americans reported that ACE levels were unrelated to the ACE*I/D polymorphism,⁴² and MacKenzie et al,³⁸ using combined segregation and linkage analysis, reported a much weaker relationship in a series of African-Caribbean families from Jamaica, with the ACE*I/D polymorphism accounting for only about 9% of the total variance of serum ACE levels. The latter study concluded that ACE levels in this population are strongly influenced by multiple quantitative trait loci. They identified one of these loci, which accounted for 27% of total variability, as being located close to or within the ACE gene, although the I/D polymorphism was excluded as causative; the other was an undescribed quantitative trait locus unlinked to the ACE gene that accounted for 52% of the variability.³⁸ Thus, the gene locus that is not linked to the ACE gene has the strongest influence in black subjects, and the ACE*I/D genotype shows a much lower correlation with circulating ACE levels in black^{38 42} compared with white populations.³⁴

Another area that remains to be explored is the relevance of HCC⁴³ in any effects mediated by the ACE*D allele. HCC has regional differences in its cardiac expression and is a more potent local converter of Ang I to Ang II than ACE. Thus, genetic mechanisms that influence expression of HCC could explain in part the importance of the ACE*D allele in cardiac disease within individuals.

Studies of ACE*I/D alleles as possible markers of outcome of cardiac and other diseases in patients at risk are needed. A concern in previous studies is that there may have been unintentional clustering of other disease risk factors in groups of patients who proved post hoc to have ACE*D alleles. One strategy that would help to reduce bias in patient selection in future prospective studies is use of the statistical technique of minimization. When this method is used, ACE*I/D alleles can be used as the basis for randomization of patients when treatment is assigned, with study groups balanced for other major disease risk factors.

It will be important to dissect the primary direct or indirect actions for disease causation from the effects superimposed on established disease for whose expression the ACE*I/D alleles serve as markers. These studies will help to show whether the D allele consistently leads to better or worse outcome, ie, whether it is a "good" or "bad" polymorphism to have.

Many drugs are available or are under development that can selectively modulate activity of ACE and other components of the renin-angiotensin-aldosterone system. Identification of mechanisms for the positive associations between ACE*I/D and disease could focus interest on important new targets for the diagnosis, clinical monitoring, and treatment of medical problems associated with ACE*I/D alleles.

	Selected Abbreviations and Acronyms

 

AGT1R = angiotensin II type 1 receptor Ang = angiotensin CAD = coronary artery disease CHD = coronary heart disease HCC = human cardiac chymase MI = myocardial infarction

	Acknowledgments

 
Dr Singer and Dr Jeffery receive support from the British Heart Foundation. We are grateful to Prof N.D. Carter, Department of Medical Genetics, for his helpful comments on the manuscript.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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				Y. Watanabe, T. Ishigami, Y. Kawano, T. Umahara, A. Nakamori, S. Mizushima, K. Hibi, I. Kobayashi, K. Tamura, H. Ochiai, et al. Angiotensin-Converting Enzyme Gene I/D Polymorphism and Carotid Plaques in Japanese Hypertension, September 1, 1997; 30(3): 569 - 573. [Abstract] [Full Text]

				K. Hibi, T. Ishigami, K. Kimura, M. Nakao, T. Iwamoto, K. Tamura, T. Nemoto, T. Shimizu, Y. Mochida, H. Ochiai, et al. Angiotensin-Converting Enzyme Gene Polymorphism Adds Risk for the Severity of Coronary Atherosclerosis in Smokers Hypertension, September 1, 1997; 30(3): 574 - 579. [Abstract] [Full Text]

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