Objective This meta-analysis attempted to derive pooled estimates for the associations between various cardiovascular-renal disorders and the deletion/insertion (D/l) polymorphism of the angiotensin converting enzyme (ACE) gene. Methods Case-control studies were combined, using the Mantel-Haenszel approach. Joint P values for continuous variables were calculated by Stouffer's method. Continuous measurements reported in different units were expressed on a percentage scale using the within-study mean of the II genotype as the denominator. Results The computerized database used for this analysis included 145 reports with an overall sample size of 49 959 subjects. Overall, possession of the D allele was associated with an increased risk of atherosclerotic and renal microvascular complications. In comparison with the II reference group, the excess risk in DD homozygotes (P < 0.001) was 32% for coronary heart disease (CHD; 30 studies), 45% for myocardial infarction (20 studies), 94% for stroke (five studies) and 56% for diabetic nephropathy (11 studies). The corresponding risk in Dl heterozygotes amounted to 11% (P = 0.02), 13% (P = 0.02), 22% (P = 0.10) and 40% (P < 0.001), respectively. Hypertension (23 studies), left ventricular hypertrophy (five studies), hypertrophic or dilated cardiomyopathy (eight studies) and diabetic retinopathy (two studies) were not related to the Dl polymorphism. Publication bias was observed for CHD, myocardial infarction and microvascular nephropathy, but not hypertension. In studies with DNA amplification in the presence of insertion-specific primers, the risk associated with the DD genotype increased to 150% [95% confidence interval (Cl) 76-256; four studies] for diabetic nephropathy, but decreased to 12% (95% Cl -3 to 28; seven studies) for CHD and 14% (95% Cl -6 to 37; four studies) for myocardial infarction. On the other hand, the pooled odds ratios did not materially change if the meta-analysis was limited to articles published in journals with an impact factor of at least 4. Furthermore, compared with the II control group, the circulating ACE levels (29 studies) were raised 58 and 31% (P< 0.001) in DD and Dl subjects, respectively. In contrast, plasma renin (10 studies), systolic and diastolic blood pressure (46 studies) and body mass index (30 studies) were not associated with the D allele. Conclusion The D allele is not associated with hypertension, but behaves as a marker of atherosclerotic cardiovascular complications and diabetic nephropathy. These associations do not necessarily imply a causal relationship and may have been inflated by publication bias. Nevertheless, their possible therapeutic implications may be subject to further investigation in prospective (intervention) studies.

The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(00)82009-7.pdf

Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators.

Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors.

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

BACKGROUND
The original report of a possible association between myocardial infarction and the insertion/deletion (I/D) polymorphism of the gene for the angiotensin-1-converting enzyme (ACE) indicated a risk ratio for myocardial infarction with the DD genotype of 1.34 (95% CI 1.05-1.70), and the association was claimed to be particularly strong in a retrospectively defined low-risk subgroup (3.2 [95% CI 1.7-5.9). Subsequent investigations reached varying conclusions, but all were small, and much larger studies were needed.


METHODS
4629 myocardial infarction cases and 5934 controls were compared. Cases were UK men aged 30-54 years and women aged 30-64 years recruited on presentation to hospital with confirmed myocardial infarction. Controls were aged 30-64 years with no history of cardiovascular disease, but were siblings or children of myocardial infarction survivors, or spouses of such relatives. All risk-ratio calculations allow for this relatedness of some of the controls. An updated meta-analysis of previous studies was also conducted.


FINDINGS
The ACE DD genotype was found in 1359 (29.4%) of the myocardial infarction cases and in 1637 (27.6%) of the controls (risk ratio 1.10 [95% CI 1.00-1.21]). The association between myocardial infarction and the DD genotype did not seem to be stronger in the subgroup defined as low risk by previously used criteria (234 [28%] of 836 cases and 911 [28%] of 3253 controls: risk ratio 1.04 [95% CI 0.87-1.24]), or in any other subgroup. Nor was the ACE I/D genotype predictive of subsequent survival.


INTERPRETATION
This study involved many more cases than any previously reported study of this question, but did not confirm the existence of any substantial association. In an updated meta-analysis of these results with those of previously published studies, the risk ratio for myocardial infarction with the DD genotype seems to lie in the range 1.0 to about 1.1. Although an increase in risk of up to about 10-15% cannot be ruled out, substantially more extreme risks can be. Moreover, there are not especially strong associations in the subgroups previously selected for emphasis. These findings illustrate the need for some studies of candidate genes to involve much larger populations than is customary, without undue emphasis on retrospectively defined subgroups.

Large-scale test of hypothesised associations between the angiotensin-1 converting enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 5000 controls

ContextA genetic basis has been identified for many medical
conditions and some molecular tests have been commercialized. However,
little attention has been given to the quality of clinical epidemiology
in molecular studies.ObjectiveTo examine the clinical epidemiological quality of
recent publications on molecular genetic analysis.DesignCross-sectional study of original research articles
published in 1995, identified by manually searching 4 general clinical
journals. Of 83 articles identified, 40 were selected for analysis;
these 40 discussed molecular genetic techniques, studied 10 or more
patients, and had inferential conclusions.Main Outcome MeasureCompliance of the selected articles with 7
methodological standards for clinical epidemiological science
(reproducibility, objectivity, delineation of case group, adequacy of
spectrum in case group, delineation of comparison group, adequacy of
comparison group, and quantitative summary of results).ResultsAmong the 40 inferential articles that studied 10 or
more patients, only 5 (12.5%) complied with all 7 applicable
standards, and 10 (25.0%) complied with all but 1 standard, whereas 25
articles (62.5%) failed to comply with 2 or more standards and 9
(22.5%) failed 4 or 5 standards. Most articles did not comply with
standards for reproducibility (n=25, 62.5%) or
objectivity (n=27, 67.5%); however, the majority of
articles did comply with standards for adequacy of case group
(n=35, 87.5%), adequacy of comparison group
(n=35, 87.5%), and quantitative summary of results
(n=36, 90%).ConclusionsDespite major laboratory advances in molecular
genetic analysis, our data suggest that reported applications in
clinical journals often have troubling omissions, deficiencies, and
lack of attention to the different, but necessary, principles of
clinical epidemiological science. Without suitable attention to
fundamental methodological standards, the expected benefits of
molecular genetic testing may not be achieved.

Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards

Background: Previous research has shown that the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is a major determinant of plasma ACE activity. It has been s...

Deletion Polymorphism of the Angiotensin I-Converting Enzyme Gene Is Associated with Increased Plasma Angiotensin-Converting Enzyme Activity but Not with Increased Risk for Myocardial Infarction and Coronary Artery Disease

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Deletion Polymorphism of the Angiotensin I-Converting Enzyme Gene Is Associated with Increased Plasma Angiotensin-Converting Enzyme Activity but Not with Increased Risk for Myocardial Infarction and Coronary Artery Disease