This meta-analysis attempted to derive pooled estimates for the associations between various cardiovascular-renal disorders and the deletion/insertion (D/I) polymorphism of the angiotensin converting enzyme (ACE) gene.
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.
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 DI 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 DI 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 (CI) 76–256; four studies] for diabetic nephropathy, but decreased to 12% (95% CI −3 to 28; seven studies) for CHD and 14% (95% CI −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 DI 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.
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.
1Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium
2Department of Hypertension, cardiovascular Institute and Fu-Wai Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
3Department of Experimental Medicine, First Medical Clinic, University of Padua, Paduia, Italy
4INSERM U358, Paris, France
5Center for Human Genetics, University of Leuven, Leuven, Belgium.
6Requests for reprints to Dr Jan A. Staessen, Klinisch Laboratorium Hypertensie, Inwendige Geneeskunde-Cardiologie, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Sponsorship: This research project has been made possible through grants from the National Fund for Scientific Research (Brussels, Belgium); J.G.W. is the recipient of a fellowship awarded by Bayer A.G., Wuppertal, Germany.