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

TLDR: The D allele is not associated with hypertension, but behaves as a marker of atherosclerotic cardiovascular complications and diabetic nephropathy, and their possible therapeutic implications may be subject to further investigation in prospective (intervention) studies.

Abstract: 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.