Association of ACE insertion or deletion polymorphisms with the risk of coronary restenosis after percutaneous coronary intervention: A meta-analysis

Abstract

Objective:

Previous case-control studies on the relationship between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and coronary restenosis did not reach the same conclusion. In the present study, we aimed to further evaluate the relationship between the ACE gene I/D polymorphisms and coronary restenosis, after percutaneous coronary intervention (PCI).

Methods:

By searching PubMed, EMBase, the Chinese Biomedical Literature Database and Wanfang database, we selected 16 case-control studies related to ACE gene I/D polymorphism and coronary restenosis after PCI. To test for heterogeneity in each study, we utilized the Q-test and I² test. To merge the odds ratio (OR) and 95% CI, we utilized the random effects model during the analyses.

Results:

The present study included 4693 subjects: 1241 patients with coronary restenosis and 3452 without coronary restenosis. By meta-analysis, we found there was significant association of ACE gene I/D polymorphism with coronary restenosis (D allele versus I allele: OR = 1.92; 95% CI (1.40–2.43); p < 0.001). A subgroup analysis, by stratification according to ethnicity, also showed that this association was found not only in the Caucasian population ((D allele versus I allele: OR = 1.94; 95% CI (1.38–2.80); p < 0.001)), but also in the Asian population ((D allele versus I allele: OR = 1.83; 95% CI (1.05–3.20); p = 0.03)). After stratification according to age, we found that the D allele carriers have a higher risk for development of coronary restenosis in subjects < 60 years old (OR = 2.13; 95% CI: 1.40–3.24; p = 0.0004); while in the subjects ⩾ 60 years old, the association was present with bordering significance (OR = 1.48; 95%CI: 0.98–2.25; p = 0.06).

Conclusions:

The present study suggested that the ACE gene I/D polymorphism was associated with coronary restenosis, regardless of age and ethnicity.

Keywords

Angiotensin-converting enzyme coronary artery disease coronary restenosis gene polymorphism meta-analysis percutaneous coronary intervention restenosis

Introduction

Coronary artery disease (CAD), including myocardial infarction, is the leading cause of death and disability in the world.^1–3 One of the standard treatments for CAD is percutaneous coronary intervention (PCI) with stent placement⁴; however, a portion of the patients with PCI treatment suffer in-stent restenosis (ISR), which is the main limitation of coronary stenting.⁵ ISR is the formation of scar tissue over the stent and can cause the opened artery to narrow again. Although the incidence of was ISR reduced recently with the application of new therapies, treatment of ISR remains a challenging clinical issue.⁶

During the past decade, there has been increasing scientific interest in understanding the complex relationship between coronary restenosis after PCI and the renin-angiotensin system (RAS).^7–9 The RAS plays an important role in blood pressure and cardiovascular homeostasis^10,11; and recently-published data indicate that angiotensin II, the main biologically-active peptide of RAS, contributes to coronary restenosis development and progression.^12,13 The production of angiotensin II is regulated by ACE, which has serum levels governed by genetic variation at the ACE locus. Previous studies indicate that certain genetic polymorphisms are recognized to be associated with the risk of coronary restenosis.^14–19 Among these genes, the ACE gene polymorphisms were considered as a risk factor of coronary restenosis in several published papers^20–34; however, the results of these studies were inconsistent. Rebrova et al.³⁴ found that ACE genetic polymorphism is associated with coronary restenosis risk. Guneri et al.³² and Okumura et al.³³ also confirmed the previous studies; however, Martínez-Ríos et al.³⁵ did not find any association between ACE gene insertion/deletion (I/D) polymorphisms and coronary restenosis risk. Therefore, we collected all published case-control studies related to the ACE I/D polymorphisms and coronary restenosis risk to perform a meta-analysis, to further explore the relationship between ACE gene polymorphisms and coronary restenosis.

Materials and methods

Literature collection and screening

We identified all the articles that reported the association of ACE polymorphisms and coronary restenosis risk. We conducted a computerized literature search of PubMed, EMBase, the Chinese Biomedical Literature Database, the Chinese CNKI, and the Wanfang database; using the terms ‘coronary restenosis’ and ‘angiotensin-converting enzyme’ or ‘ACE’, and ‘polymorphism’ or single nucleotide polymorphism (‘SNP’), or ‘genotype’, or ‘insertion/deletion’ or ‘I/D’, or ‘D/I’, ‘D/D’ or ‘I/I’; without any restriction on language or publication year. We expected that the included studies must meet to the following criteria:

Case-control or cohort studies on the relation between ACE polymorphism and coronary restenosis;

Similar themes and methods; and

Sufficient data upon genotype and alleles counts.

Literature were excluded if relevant data were not available or there was heterogeneity of gene polymorphisms in the control population.

Quality assessment and data extraction

Two reviewers (H-W Miao and H Gong) used a standard approach, according to the above-mentioned inclusion criteria, independently evaluating the studies and extracting the data (Table 1). Discrepancies were resolved through discussion. The methodological quality of the included studies was assessed by using the Cochrane Handbook 5.2³⁶ quality evaluation criteria. We extracted the following information for each study: The first author’s last name, year of publication, ethnicity of the study participants, numbers of cases and controls, and frequency of insertion or deletion genotypes. Hardy-Weinberg equilibrium was assessed, using the χ² test.

Table 1.

The characteristics of included studies.

Authors	Year published	Country	Ethnicity	Mean patient age (yrs)	Definition of restenosis	H-WE	N, Cases/controls	OR	95% CI		Log (OR)	SE
Amant et al.	1997	France	Cs	60.0	> 50%	Y	59/99	2.00	1.03	3.88	0.69	0.34
Ferrari et al.	2002	Germany	Cs	61.0	> 50%	Y	39/115	2.16	0.85	5.49	0.77	0.48
Gomma et al.	2002	UK	Cs	59.4	> 50%	Y	60/144	1.57	0.97	2.54	0.45	0.25
Guarda et al.	1999	Chile	Cs	NA	> 50%	Y	22/26	3.25	1.39	7.61	1.18	0.43
Guneri et al.	2005	Turkey	Cs	59.6	> 50%	Y	48/48	1.03	0.56	1.87	0.03	0.31
Gürlek et al.	2000	Turkey	Cs	53.0	> 50%	Y	51/107	6.29	1.80	22.05	1.84	0.64
Jørgensen et al.	2001	Denmark	Cs	59.0	> 50%	Y	49/320	3.33	1.08	10.27	1.20	0.57
Koch et al.	2000	Germany	Cs	62.9	> 50%	Y	513/1043	1.00	0.86	1.16	0.00	0.08
Okumura et al.	2002	Japan	As	64.3	> 50%	Y	19/27	0.63	0.21	1.91	–0.46	0.57
Qu et al.	2002	China	As	68.0	> 50%	Y	43/85	2.21	1.26	3.90	0.80	0.29
Ryu et al.	2002	Korea	As	59.5	> 50%	Y	64/191	1.09	0.34	3.47	0.09	0.59
Taniguchi et al.	2001	Japan	As	65.2	> 50%	Y	26/41	1.69	0.83	3.43	0.53	0.36
Rebrova et al.	2012	Russia	Cs	NA	> 50%	Y	101/232	2.83	1.11	7.22	1.04	0.48
Lv et al.	2012	China	As	58.8	> 50%	Y	81/315	3.81	2.30	6.31	1.34	0.26
Martínez-Ríos	2008	Mexico	Cs	59.1	> 50%	Y	66/102	2.17	1.49	3.16	0.77	0.19

As: Asian; Cs: Caucasian; H-WE: Hardy-Weinberg equilibrium; OR: odds ratio; NA: not available; SE: standard error; Y: yes; yrs: years.

Statistical analysis

We used RevMan 5.2 software, provided by the Cochrane Collaboration, to perform the meta-analysis. We used Q-test and I² test to examine the heterogeneity between each study. The odds ratio (OR) and its 95% CI were utilized for efficacy analysis statistics. We selected either the fixed or random-effects model, to merge the OR according to the I² value. Sensitivity analyses and publication bias tests were performed according to previous literature. We considered a P < 0.05 as a significant difference.

Results

Study identification

As shown in Figure 1, we preliminarily detected 144 articles in the literature: 104 were excluded, because of only gene expression analysis not relevant to coronary restenosis, and no ACE genotype data; and 24 studies were further excluded because of being only a review paper, no control group, and/or being duplicate publications. Therefore, a total of 16 journal literature articles,^20–35 with a total of 4693 subjects (1241 patients with coronary restenosis and 3452 subjects without coronary restenosis), were included in this research.

Figure 1.

Flow diagram of study identification.

Quantitative synthesis

As shown in Figure 2, the heterogeneity test of the various studies revealed there were heterogeneous results (I² = 77%; p < 0.0001); therefore, we used the random effects model in our analysis. We found a significant difference between ACE I/D polymorphisms and the risk for coronary restenosis. The D allele carriers had a 1.92-fold increased risk for coronary restenosis, compared to the I allele carriers (OR = 1.92; 95% CI 1.40–2.63; p < 0.001). Also, subgroup analysis by stratification according to ethnicity (Figure 3) showed that this association was found not only in the Caucasian population ((D allele versus I allele: OR = 1.94; 95% CI (1.38–2.80); p < 0.001)), but also in the Asian population ((D allele versus I allele: OR = 1.83; 95% CI (1.05–3.20); p = 0.03)). After stratification according to age (Figure 4), we found that D allele carriers have a higher risk for development of coronary restenosis in subjects < 60 years old (OR = 2.13; 95%CI: 1.40–3.24; p = 0.0004); while in subjects with ⩾ 60 years of age, the association was present at a borderline significance (OR = 1.48; 95%CI: 0.98–2.25; p = 0.06).

Figure 2.

Forest plot of coronary restenosis risk associated with ACE I/D polymorphisms in the total population. The squares and horizontal lines correspond to the study-specific OR and 95% CI, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI.

Figure 3.

Forest plot of coronary restenosis risk associated with ACE I/D polymorphism in subgroup analysis by stratification according to the ethnicity. The squares and horizontal lines correspond to the study-specific OR and 95% CI, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. (a) Caucasian population; (b) Asian population.

Figure 4.

Forest plot of coronary restenosis risk associated with ACE I/D polymorphism in a subgroup analysis by stratification according to the age. The squares and horizontal lines correspond to the study-specific OR and 95% CI, respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. (a) < 60 years old and (b) ⩾ 60 years old.

Publication bias analysis

RevMan 5.0 software was used to analyze the publication bias; a funnel plot (Figure 5) showed that the points were evenly distributed and symmetrical, and most of the points were within the 95% CI. The shape of the funnel plots showed no obvious asymmetry. The result of Egger’s test did not show statistical evidence for bias. It indicated that there was no publication bias and that the result of the study is credible.

Figure 5.

Begg’s funnel plot for publication bias test. Each circle denotes an independent study for the indicated association. Log[OR] is the natural logarithm of OR. The horizontal line represents the mean effect size.

Sensitivity analysis

We deleted one single study from the overall pooled analysis each time, to check the influence of the removed data set to the overall ORs. The pooled ORs and 95% CIs were not significantly altered when any part of the study was omitted, which indicated that any single study had little impact on the overall ORs.

Discussion

In the present study, we performed a meta-analysis to evaluate the association of ACE gene I/D polymorphisms with coronary restenosis. We found a significant association of ACE gene polymorphisms with coronary restenosis.

Restenosis after PCI is an important clinical problem. The formation of restenosis may result from the following mechanisms:

A response to injury of the vessel wall;

A platelet aggregation;

A thrombus formation;

A liberation of growth factors;

Cellular hyperplasia involving predominantly smooth muscle proliferation and migration; and

Intercellular matrix formation.

So far, the etiological basis of restenosis is only partly understood. The genetic polymorphisms in the ACE gene are considered to be associated with coronary restenosis. ACE is a core factor for the production of angiotensin II; and the degradation of bradykinin³⁷ and angiotensin II plays a pivotal role in the restenosis process.³⁸ Previous studies indicate that high ACE levels may increase the risk of coronary thrombosis.³⁹ And ACE gene I/D polymorphisms have consistently been found associated with differential plasma ACE levels.⁴⁰ Furthermore, serum plasma activity of ACE is thought to play a major role in the development of restenosis after coronary stent implantation.^41,42 Recently, a number of articles in the literature reported on the relationship between ACE I/D polymorphisms and coronary restenosis risk^20–35; however, the results are inconsistent or even contradictory. This discrepancy may result from the small sample size, ethnic difference, false positive results, and/or study design in each study.

In the present study, we performed a meta-analysis to reveal the association of ACE I/D polymorphisms with coronary restenosis. Our results showed that ACE gene I/D polymorphisms were associated with the susceptibility of coronary restenosis, with the D allele carriers having a 1.92-fold increase in risk for restenosis, compared to the I allele carriers; however, there is still a need for further research and screening of the etiological relationships between the functional polymorphism loci of the ACE gene and the susceptibility to coronary restenosis.

There are still several limitations, when interpreting these results. On the one hand, all the subjects involved in our study are of different ethnicity. On the other hand, the heterogeneity found between each study may result from the different research methods.

In conclusion, the present study suggested that there is an association between the ACE gene I/D polymorphisms and coronary restenosis.

Footnotes

Conflict of interest

The authors declare that there are no conflicts of interest.

Funding statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Maiese

. Turning up the pressure on vascular disease. Curr Neurovasc Res 2014; 11: 291–293.

Pérez-Castrillon

Dueñas-Laita

. New approaches to atherosclerotic cardiovascular disease: The potentialities of torcetrapib. Recent Pat Cardiovasc Drug Discov 2006; 1: 109–114.

Min

Wann

. Indications for coronary and cardiac computed tomographic angiography. Cardiol Rev 2007; 15: 87–96.

Deo

Sharma

Shah

. Minimally-invasive direct coronary artery bypass graft surgery or percutaneous coronary intervention for proximal left anterior descending artery stenosis: A meta-analysis. Ann Thorac Surg 2014; 97: 2056–2065.

Kurz

Eberli

. Medical therapy of coronary artery disease after percutaneous intervention. Curr Opin Pharmacol 2013; 13: 287–293.

Zheng

Liu

Wang

. Systematic review of Chinese herbal medicines for preventing in-stent coronary restenosis after percutaneous coronary intervention. Evid Based Complement Alternat Med 2012; 2012: 253409.

Wijpkema

Van Haelst

Monraats

. Restenosis after percutaneous coronary intervention is associated with the angiotensin-II Type-1 receptor 1166A/C polymorphism; but not with polymorphisms of angiotensin-converting enzyme, angiotensin-II receptor, angiotensinogen nor heme oxygenase-1. Pharmacogenet Genomic 2006; 16: 331–337.

Ribichini

Ferrero

Rognoni

. Angiotensin antagonism in coronary artery disease: Results after coronary revascularisation. Drugs 2005; 65: 1073–1096.

Toyofyuku

Imazu

Sumii

. Influence of angiotensinogen M253T gene polymorphism and an angiotensin-converting enzyme inhibitor on restenosis after percutaneous coronary intervention. Atherosclerosis 2002; 160: 339–344.

10.

Balakumar

Jagadeesh

. A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology. Cell Signal 2014; 26: 2147–2160.

11.

Patel

Velkoska

Freeman

. From gene to protein: Experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front Physiol 2014; 5: 227.

12.

Kondo

Ninomiya

Hata

. Angiotensin I-converting enzyme gene polymorphism enhances the effect of hypercholesterolemia on the risk of coronary heart disease in a general Japanese population: The Hisayama study. J Atheroscler Thromb 2015; 22: 390–403.

13.

McAlister

Majumdar

Lin

. Cholesterol end points predict outcome in patients with coronary disease: Quality improvement metrics from the Enhancing Secondary Prevention in Coronary Artery Disease (ESP-CAD) trial. Can J Cardiol 2014; 30: 1627–32.

14.

Verschuren

Trompet

Postmus

. Systematic testing of literature-reported genetic variation associated with coronary restenosis: Results of the GENDER study. PLoS One 2012; 7: e42401.

15.

Kaestner

Patsouras

Spathas

. Lack of association between the cholesteryl ester transfer protein gene-TaqIB polymorphism and coronary restenosis following percutaneous transluminal coronary angioplasty and stenting: A pilot study. Angiology 2010; 61: 338–343.

16.

Hamann

Gomma

Schröder

. A frequent toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med 2005; 83: 478–485.

17.

Bonnici

Keavney

Collins

. Angiotensin-converting enzyme insertion or deletion polymorphism and coronary restenosis: Meta-analysis of 16 studies. Brit Med J 2002; 325: 517–520.

18.

Bauters

Amouyel

Bertrand

. ACE gene polymorphism and coronary restenosis. Semin Interv Cardiol 1999; 4: 145–149.

19.

Guarda

Fajuri

Marchant

. D/D genotype of the gene for angiotensin-converting enzyme as a risk factor for post-stent coronary restenosis. Rev Esp Cardiol 1999; 52: 475–480.

20.

Amant

Bauters

Bodart

. D allele of the angiotensin I-converting enzyme is a major risk factor for restenosis after coronary stenting. Circulation 1997; 96: 56–60.

21.

Guarda

Fajuri

Marchant

. D/D genotype of the gene for angiotensin-converting enzyme as a risk factor for post-stent coronary restenosis. Rev Esp Cardiol 1999; 52: 475–480.

22.

Gürlek

Güleç

Karabulut

. Relation between the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and restenosis after coronary stenting. J Cardiovasc Risk 2000; 7: 403–407.

23.

Koch

Kastrati

Mehilli

. I/D polymorphism of the angiotensin I-converting enzyme gene is not associated with restenosis after coronary stent placement. Circulation 2000; 102: 197–202.

24.

Jørgensen

Kelbaek

Helqvist

. Predictors of coronary in-stent restenosis: Importance of angiotensin-converting enzyme gene polymorphism and treatment with angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2001; 38: 1434–1439.

25.

Taniguchi

Yamazaki

Wagatsuma

. The DD genotype of angiotensin-converting enzyme polymorphism is a risk factor for coronary artery disease and coronary stent restenosis in Japanese patients. Japan Circ J 2001; 65: 897–900.

26.

Ferrari

Mudra

Grip

. Angiotensin-converting enzyme insertion/deletion polymorphism does not influence the restenosis rate after coronary stent implantation. Cardiology 2002; 97: 29–36.

27.

Ryu

Cho

Park

. Renin-angiotensin-aldosterone system (RAAS) gene polymorphism, as a risk factor of coronary in-stent restenosis. Yonsei Med J 2002; 43: 461–472.

28.

Gomma

Elrayess

Knight

. The endothelial nitric oxide synthase (Glu298Asp and -786T>C) gene polymorphisms are associated with coronary in-stent restenosis. Eur Heart J 2002; 23: 1955–1962.

29.

Zhao

Liu

. Relationship between angiotensin-1 converting enzyme gene polymorphism and in-stent restenosis. Chinese Med. J. 2002; 82: 474–476.

30.

Okumura

Sone

Kondo

. Quinapril prevents restenosis after coronary stenting, in patients with angiotensin-converting enzyme D allele. Circ J 2002; 66: 311–316.

31.

. Association study of angiotensin-converting enzyme gene I/D polymorphism and restenosis after coronary stent placement. Molecular Cardiology Journal of China 2012; 12: 76–78.

32.

Guneri

Baris

Aytekin

. The relationship between angiotensin-converting enzyme gene polymorphism, coronary artery disease and stent restenosis: The role of angiotensin-converting enzyme inhibitors in stent restenosis, in patients with diabetes mellitus. Int Heart J 2005; 46: 889–897.

33.

Okumura

Sone

Kondo

. Quinapril prevents restenosis after coronary stenting in patients with angiotensin-converting enzyme D allele. Circ J 2002; 66: 311–316.

34.

Rebrova

TIu

Muslimova

Afanas’ev

. D allele of the angiotensin-converting enzyme gene is a putative risk factor of restenosis after coronary stenting in patients with coronary heart disease. Klin Med (Mosk) 2012; 90: 24–26.

35.

Martínez-Ríos

Peña-Duque

Fragoso

. No association found between the insertion/deletion of a 287-bp Alu repeat sequence, within intron 16 of the angiotensin I-converting enzyme (ACE) gene in Mexican patients; and binary restenosis after coronary stenting. Clin Chim Acta 2008; 397: 65–67.

36.

Huang

Wang

Chen

Wei

Chen

. Meta-analysis on effect of compound Danshen injection in treating neonatal hypoxic-ischemic encephalopathy. Zhongguo Zhong Yao Za Zhi. 2015; 40(1): 141–8.

37.

Guiducci

Fatini

Rogai

. Angiotensin-converting enzyme in systemic sclerosis: From endothelial injury to a genetic polymorphism. Ann NY Acad Sci 2006; 1069: 10–19.

38.

Takemoto

Egashira

. Vascular remodeling and angiotensin II. Nihon Rinsho 1999; 57: 1158–1163.

39.

Gensini

Comeglio

Colella

. Classical risk factors and emerging elements in the risk profile for coronary artery disease. Eur Heart J 1998; 19: A53–61.

40.

Fan

. Associations of ACE gene insertion/deletion polymorphism, ACE activity and ACE mRNA expression with hypertension in a Chinese population. PLoS One 2013; 8: e75870.

41.

Ribichini

Ferrero

Piessens

. Intracoronary beta-irradiation prevents excessive in-stent neointimal proliferation in de novo lesions of patients with high plasma ACE levels: The BetAce randomized trial. Cardiovasc Revasc Med 2005; 6: 7–13.

42.

Ribichini

Ferrero

Matullo

. Association study of the I/D polymorphism and plasma angiotensin-converting enzyme (ACE) as risk factors for stent restenosis. Clin Sci (Lond) 2004; 107: 381–389.