ACE (I/D) polymorphism and response to treatment in coronary artery disease: a comprehensive database and meta-analysis involving study quality evaluation

Abstract

Background: The role of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in modifying the response to treatment modalities in coronary artery disease is controversial.

Methods: PubMed was searched and a database of 58 studies with detailed information regarding ACE I/D polymorphism and response to treatment in coronary artery disease was created. Eligible studies were synthesized using meta-analysis methods, including cumulative meta-analysis. Heterogeneity and study quality issues were explored.

Results: Forty studies involved invasive treatments (coronary angioplasty or coronary artery by-pass grafting) and 18 used conservative treatment options (including anti-hypertensive drugs, lipid lowering therapy and cardiac rehabilitation procedures). Clinical outcomes were investigated by 11 studies, while 47 studies focused on surrogate endpoints. The most studied outcome was the restenosis following coronary angioplasty (34 studies). Heterogeneity among studies (p < 0.01) was revealed and the risk of restenosis following balloon angioplasty was significant under an additive model: the random effects odds ratio was 1.42 (95% confidence interval:1.07-1.91). Cumulative meta-analysis showed a trend of association as information accumulates. The results were affected by population origin and study quality criteria. The meta-analyses for the risk of restenosis following stent angioplasty or after angioplasty and treatment with angiotensin-converting enzyme inhibitors produced non-significant results. The allele contrast random effects odds ratios with the 95% confidence intervals were 1.04(0.92-1.16) and 1.10(0.81-1.48), respectively. Regarding the effect of ACE I/D polymorphism on the response to treatment for the rest outcomes (coronary events, endothelial dysfunction, left ventricular remodeling, progression/regression of atherosclerosis), individual studies showed significance; however, results were discrepant and inconsistent.

Conclusion: In view of available evidence, genetic testing of ACE I/D polymorphism prior to clinical decision making is not currently justified. The relation between ACE genetic variation and response to treatment in CAD remains an unresolved issue. The results of long-term and properly designed prospective studies hold the promise for pharmacogenetically tailored therapy in CAD.

Figure 1

Flow chart of retrieved studies and studies excluded, with specification of reasons.

Figure 2

Random effects (RE) odds ratio (OR) estimates with the corresponding 95% confidence interval (CI) of the allele contrast (ACE D vs. I) for restenosis a) after PTCA-balloon, and b) after PTCA-STENT. The OR estimate of each study is marked with a solid black square. The size of the square represents the weight that the corresponding study exerts in the meta-analysis. The confidence intervals of pooled estimates are displayed as a horizontal line through the diamond. The horizontal axis is plotted on a log scale.

Figure 3

Cumulative meta-analysis of the allele contrast (ACE D vs. I) for restenosis a) after PTCA-balloon, and b) after PTCA-STENT. The random effects pooled odds ratio (OR) with the corresponding 95% confidence interval (CI) at the end of each year-information step is shown.

Figure 4

Recursive cumulative meta-analysis of the allele contrast (ACE D vs. I) for restenosis a) after PTCA-balloon, and b) after PTCA-STENT. The relative change in random effects pooled odds ratio (OR) in each information step (OR in next year/OR in current year) for the allele contrast is shown.