Abstract
Objective
To assess the association between genotype at the insertion or deletion polymorphism of the angiotensin converting enzyme gene and risk of coronary restenosis after percutaneous coronary intervention.
Design
Meta-analysis of studies before July 2001 that reported on these genotypes and risk of coronary restenosis after a percutaneous coronary intervention, with or without coronary stenting.
Results
16 studies, involving 4631 patients undergoing a percutaneous coronary intervention, yielded 1683 patients with restenosis after a mean weighted follow up of 5.5 months. The combined odds ratio for restenosis in people with the DD genotype was 1.23 (99% confidence interval 1.03 to 1.46). When studies were grouped by size, however, the combined odds ratios for restenosis in people with the DD genotype were 1.94 (1.39 to 2.71) for studies with less than 100 cases, 1.33 (0.92 to 1.93) for studies with 100-200 cases, and 0.92 (0.72 to 1.18) for studies with more than 200 cases (trend P=0.02). Similarly, when studies were grouped by genotyping procedures, significantly larger odds ratios were found in the studies that did not conceal disease status from laboratory staff and in the studies that did not use a second polymerase chain reaction amplification to reduce genetic mistyping.
Conclusion
Compared with other studies, larger and more rigorous studies show a weaker association between the angiotensin converting enzyme gene DD genotype and restenosis. Publication bias or detection biases can produce artefactual associations at least as large as those that might be expected for common polymorphisms in complex diseases, suggesting the need for larger and more rigorous genetic epidemiological investigations than are now customary.
What is already known on this topic
Restenosis after a percutaneous coronary intervention is one of the principal limitations of the technique
Genotype at the angiotensin converting enzyme insertion or deletion polymorphism is proposed to be important in restenosis
What this study adds
Weaker associations between the angiotensin converting enzyme DD genotype and restenosis were found in larger and more rigorous studies than in other studies
Publication bias or detection biases, or both, can produce artefactual associations at least as large as those that might be expected for common polymorphisms in complex diseases
Introduction
Restenosis after a percutaneous coronary intervention is one of the principal limitations of this technique, occurring in up to 50% of patients undergoing the procedure without stenting and in about 20% of patients receiving stents.1 Despite a lack of good evidence that susceptibility to restenosis is genetically determined, several studies have investigated polymorphisms that might be associated with restenosis. As the angiotensin converting enzyme insertion or deletion (I/D) polymorphism is strongly associated with plasma and cellular angiotensin converting enzyme concentrations, it has been considered a strong candidate.2 It has been suggested that the incidence of coronary restenosis after a percutaneous coronary intervention is much higher in patients with the angiotensin converting enzyme DD genotype (which is associated with particularly high plasma angiotensin converting enzyme levels) than in others, but published observational studies are conflicting.3–18 To help clarify the evidence we considered all available relevant studies in a meta-analysis.
Methods
We sought studies published before July 2001 of the angiotensin converting enzyme insertion or deletion polymorphism and coronary restenosis after a percutaneous coronary intervention, with or without coronary stenting, by computer based searches (Medline, Embase, PubMed, Web of Science), reviews of reference lists, hand searching relevant journals, and correspondence with authors. For the electronic searches we used combinations of key words relating to the angiotensin converting enzyme gene (for example, angiotensin converting enzyme, ACE, polymorphism, insertion/deletion, I/D, D/I) and to restenosis (for example, coronary, restenosis, percutaneous, angioplasty, PTCA, stent, stenting). We included all identified studies. Articles in languages other than English were translated.
From each study we abstracted (supplemented by correspondence with investigators) geographical location, race of participants, numbers of cases and controls, the coronary intervention procedure, definition of restenosis, frequency of insertion or deletion genotypes, genotyping methods and laboratory procedures, mean age, and duration of follow up.
We estimated odds ratios by comparing cases who developed coronary restenosis after a percutaneous coronary intervention with controls who did not within the same study. We did this under the prior hypothesis that individuals who were homozygous for the angiotensin converting enzyme D allele were predisposed to restenosis compared with those with the ID or II genotypes.19
Results
We identified 16 relevant studies concerning a percutaneous coronary intervention, 11 without stenting (2535 patients) and five with stenting (2096 patients), yielding 4631 patients (94% white) undergoing such interventions.3–18 All the studies used quantitative computer assisted methods to define restenosis as a narrowing of the coronary diameter by 50% or more at follow up compared with the minimal luminal diameter immediately after intervention. Overall, 1683 of these patients (mean age 60 years) developed coronary restenosis after a mean weighted follow up of 5.5 months. The studies were conducted in Australia, Chile, France, Germany, Italy, Japan, Spain, Turkey, the United Kingdom, and the United States.3–18 Following correspondence with the authors, it was confirmed that genotyping had been performed by staff unaware of the disease status of the patients in four of the five studies with more than 100 cases,6 16–18 compared with only two of the 11 studies with less than 100 cases.4 8
Overall, the combined odds ratio for restenosis in people with the DD genotype was 1.23 (99% confidence interval 1.03 to 1.46; test for heterogeneity χ=24.1, df=15, P=0.06: fig 1). We found no significant heterogeneity between studies of percutaneous coronary intervention with stenting and those without stenting (combined odds ratios for the DD genotype of 1.17 v 1.27 respectively; χ=0.23, df=1, P=0.6). When studies were grouped by size, however, the combined odds ratios for restenosis were 1.94 (1.39 to 2.71) for the 11 studies with less than 100 cases,3–5 7–9 11–15 1.33 (0.92 to 1.93) for the three studies with 100-200 cases,6 10,16 and 0.92 (0.72 to 1.18) for the two studies with more than 200 cases (fig 2).17 18 A test for trend across these three groups of studies was significant (χ=5.6, df=1, P=0.02). Similar results were observed when odds ratios for restenosis were calculated per D allele in these three groups (1.74 v 1.00 v 0.98, respectively). When studies were grouped by genotyping procedures, significantly larger odds ratios were observed in the studies that did not conceal disease status from laboratory staff (combined odds ratios for the DD genotype of 1.87 v 1.02 respectively, χ=9.7, df=1, P=0.002)3,5 7,9–15 and in the studies that did not use a second polymerase chain reaction amplification to reduce mistyping of angiotensin converting enzyme ID heterozygotes as DD (1.55 v 1.13, respectively; χ=4.05, df=1, P=0.03).3 5–7 10,12–14
Figure 1.
Meta-analysis of 16 published studies of angiotensin converting enzyme insertion or deletion polymorphism and coronary restenosis
Figure 2.
Meta-analysis of published studies of angiotensin converting enzyme insertion or deletion polymorphism and coronary restenosis grouped by size
Discussion
Weaker associations between the angiotensin converting enzyme DD genotype and restenosis were found in larger and more rigorous studies than in other studies. We had observed a similar trend in published studies of the angiotensin converting enzyme DD genotype and myocardial infarction.19 These findings have important implications for genetic epidemiology, suggesting that publication bias or detection biases can produce artefactual associations at least as large as those that might be realistically expected for common polymorphisms in complex diseases.
Acknowledgments
We thank the investigators for supplying additional information and Alison Palmer for plotting the figures. RC holds a British Heart Foundation personal chair. JD holds the Raymond and Beverly Sackler Research Award in the Medical Sciences.
Footnotes
Funding: FB was supported by a Rhodes scholarship.
Competing interests: None declared.
References
- 1.Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994;331:489–495. doi: 10.1056/NEJM199408253310801. [DOI] [PubMed] [Google Scholar]
- 2.Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51:197–205. [PMC free article] [PubMed] [Google Scholar]
- 3.Ohishi M, Fujii K, Minamino T, Higaki J, Kamitani A, Rakugi H, et al. A potent genetic risk factor for restenosis [letter] Nat Genet. 1993;5:324–325. doi: 10.1038/ng1293-324. [DOI] [PubMed] [Google Scholar]
- 4.Beohar N, Damaraju S, Prather A, Yu QT, Raizner A, Kleiman NS, et al. Angiotensin-I converting enzyme genotype DD is a risk factor for coronary artery disease. J Investig Med. 1995;43:275–280. [PubMed] [Google Scholar]
- 5.Kamitani A, Rakugi H, Higaki J, Ohishi M, Shi SJ, Takami S, et al. Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis. Hypertension. 1995;25:950–953. doi: 10.1161/01.hyp.25.5.950. [DOI] [PubMed] [Google Scholar]
- 6.Samani NJ, Martin DS, Brack M, Cullen J, Chauhan A, Lodwick D, et al. Insertion/deletion polymorphism in the angiotensin-converting enzyme gene and risk of restenosis after coronary angioplasty. Lancet. 1995;345:1013–1016. doi: 10.1016/s0140-6736(95)90756-4. [DOI] [PubMed] [Google Scholar]
- 7.Van Bockxmeer FM, Mamotte CD, Gibbons FA, Burke V, Taylor RR. Angiotensin-converting enzyme and apolipoprotein E genotypes and restenosis after coronary angioplasty. Circulation. 1995;92:2066–2071. doi: 10.1161/01.cir.92.8.2066. [DOI] [PubMed] [Google Scholar]
- 8.Kaski JC, Zhang Y, Calvino R, Vasquez-Rodriquez JM, Castro-Beiras A, Jeffrey S, et al. Angiotensin-converting enzyme insertion/deletion polymorphism and restenosis after coronary angioplasty in unstable angina pectoris. Am J Cardiol. 1996;77:875–877. doi: 10.1016/s0002-9149(97)89187-4. [DOI] [PubMed] [Google Scholar]
- 9.Amant C, Bauters C, Bodart JC, Lablanche JM, Grollier G, Damchin N, et al. D allele of the angiotensin I-converting enzyme is a major risk factor for restenosis after coronary stenting [see comments] Circulation. 1997;96:56–60. doi: 10.1161/01.cir.96.1.56. [DOI] [PubMed] [Google Scholar]
- 10.Hamon M, Amant C, Bauters C, Richard F, Helbecque N, Passard F, et al. Dual determination of angiotensin-converting enzyme and angiotensin-II type 1 receptor genotypes as predictors of restenosis after coronary angioplasty. Am J Cardiol. 1998;81:79–81. doi: 10.1016/s0002-9149(97)00852-7. [DOI] [PubMed] [Google Scholar]
- 11.Ribichini F, Steffenino G, Dellavalle A, Colajanni E, Camilla T, Vado A, et al. Plasma activity and insertion/deletion polymorphism of angiotensin I-converting enzyme: a major risk factor and a marker of risk for coronary stent restenosis. Circulation. 1998;97:147–154. doi: 10.1161/01.cir.97.2.147. [DOI] [PubMed] [Google Scholar]
- 12.Gensini F, Battaglini B, Fatini C, Guazzelli R, Falai M, Chioccioli M, et al. Polimorfismo I/D del gene ACE e A1166C del gene AT1R quali fattori di rischio di restenosi dopo angioplastica coronarica. Minerva Cardioangiol. 1999;47:516. [PubMed] [Google Scholar]
- 13.Guarda E, Fajuri A, Marchant E, Martinez A, Jalil J, Illanes G, et al. D/D genotype of the gene for angiotensin converting enzyme as a risk factor for post-stent coronary restenosis [see comments] Rev Esp Cardiol. 1999;52:475–480. doi: 10.1016/s0300-8932(99)74954-7. [DOI] [PubMed] [Google Scholar]
- 14.Okamura A, Ohishi M, Rakugi H, Katsuya T, Yanagitani Y, Takiuchi S, et al. Pharmacogenetic analysis of the effect of angiotensin-converting enzyme inhibitor on restenosis after percutaneous transluminal coronary angioplasty. Angiology. 1999;50:811–822. doi: 10.1177/000331979905001005. [DOI] [PubMed] [Google Scholar]
- 15.Gürlek A, Güleç S, Karabulut H, Bokesoy I, Tuter E, Pornir G, et al. Relation between the insertion/deletion polymorphism of the angiotensin I converting enzyme gene and restenosis after coronary stenting. J Cardiovascular Risk. 2000;7:403–407. doi: 10.1177/204748730000700602. [DOI] [PubMed] [Google Scholar]
- 16.Völzke H, Hertwig S, Rettig R, Motz W. The angiotensinogen gene 235T variant is associated with an increased risk of restenosis after percutaneous transluminal coronary angioplasty. Clin Sci. 2000;99:19–25. [PubMed] [Google Scholar]
- 17.Koch W, Kastrati A, Mehilli J, Bottiger C, van Beckerlath N, Schornig A. Insertion/Deletion polymorphism of the angiotensin I-converting enzyme gene is not associated with restenosis after coronary stent placement. Circulation. 2000;102:197–202. doi: 10.1161/01.cir.102.2.197. [DOI] [PubMed] [Google Scholar]
- 18.Zee RYL, Fernandez-Ortiz A, Macaya C, Pintor E, Lindpaintner K, Fernandez-Cruz A. ACE D/I polymorphism and incidence of post-PTCA restenosis: a prospective, angiography-based evaluation. Hypertension. 2001;37:851–855. doi: 10.1161/01.hyp.37.3.851. [DOI] [PubMed] [Google Scholar]
- 19.Keavney B, McKenzie C, Parish S, Palmer A, Clark S, Youngman L, et al. for the International Studies of Infarct Survival (ISIS) Collaborators. Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls Lancet 2000355434–442. [DOI] [PubMed] [Google Scholar]