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A Meta-analysis

Elias Zintzaras, MSc, PhD; Gowri Raman, MD; Georgios Kitsios, MD; Joseph Lau, MD

Arch Intern Med. 2008;168(10):1077-1089.

Background  Many studies have investigated the association between the angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphic variant and coronary artery disease (CAD). However, the evidence is inadequate to draw robust conclusions because most studies were generally small and conducted in heterogeneous samples. To shed light on these inconclusive findings, we conducted a meta-analysis of studies relating the ACE I/D polymorphic variant to the risk of CAD.

Methods  We searched the PubMed database for English-language articles on CAD in humans. We estimated summary odds ratios and explored potential sources of heterogeneity and bias.

Results  The 118 studies chosen for the analysis involved 43 733 cases with CAD and 82 606 controls. The heterogeneity between studies was significant. When we compared homozygotes with the D and I alterations, the ACE I/D polymorphic variant was associated with a 25% increased risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.16-1.35). Subgroup analyses for myocardial infarction, diabetes mellitus, male sex, white race, East Asian subjects, and Turkish subjects showed significant associations. No association was found in other racial/ethnic groups, in women, in premature cases, or in cases with low levels of risk factors. The major sources of heterogeneity were due to racial/ethnic diversity, genotyping procedure, and age matching. Cumulative meta-analysis for the allelic contrast showed a trend of association as information accumulated. There was a differential magnitude of effect in large vs small studies.

Conclusions  The meta-analysis demonstrated evidence of a modest positive association between ACE I/D polymorphic variant and CAD. The meta-analysis also highlights the heterogeneity of reported results, considerable gaps in research, and the need for future studies focused on certain high-risk patient populations.

Author Affiliations: Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts (Drs Zintzaras, Raman, and Lau); and Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece (Drs Zintzaras and Kitsios).