Meta-analysis of the association between angiotensin-converting enzyme I/D polymorphism and aortic aneurysm risk

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1 545557JRA / Journal of the Renin-Angiotensin-Aldosterone SystemSong et al. research-article2014 Original Article Meta-analysis of the association between angiotensin-converting enzyme I/D polymorphism and aortic aneurysm risk Journal of the Renin-Angiotensin- Aldosterone System 2015, Vol. 16(4) The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / jra.sagepub.com Yan Song 1, Renying Miao 1, Hanjie Wang 1, Xiaoyu Qin 1, Yonggan Zhang 1, Chaofeng Miao 1 and Zifan Wang 1 Abstract Background: Angiotensin-converting enzyme (ACE) I/D polymorphism has been indicated to be correlated with aortic aneurysm (AA) susceptibility, but study results are still debatable. Thus, a meta-analysis was conducted. Methods: Databases including PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) were searched. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results: Ten studies with 3557 cases and 5231 controls were included in this meta-analysis. The association between ACE I/D genotype and AA risk was significant (OR=1.30; 95%CI, ; p<0.01; I 2 =68%). When stratified by ethnicity, a significantly elevated risk was observed in Caucasians (OR=1.31; 95%CI, ; p<0.01; I 2 =71%). In the abdominal AA subgroup, a significantly increased risk was observed (OR=1.29; 95%CI, ; p=0.02; I 2 =73%). However, ACE I/D polymorphism was not associated with thoracic AA risk (OR=1.33; 95%CI, ; p=0.21; I 2 =52%). Subgroup analysis on blood pressure status showed that an increased risk was found in hypertensive patients (OR=1.52; 95%CI, ; p=0.04; I 2 =0%) but not in normotensive subjects (OR=1.46; 95%CI, ; p=0.30; I 2 =25%). Conclusions: In conclusion, this meta-analysis suggested that ACE I/D polymorphism is a risk factor for AA. Keywords Aortic aneurysm, ACE, meta-analysis, genetics Introduction Aortic aneurysm (AA) is a potentially serious condition that can lead to death if it ruptures. Although it is well established that advanced age, smoking, and hypertension are associated with increased risk of AA, a detailed etiology of AA is still unclear. In the past three decades, genetic association studies have revealed a considerable number of candidate loci and genes for AA. 1 Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase widely distributed on the surface of endothelial and epithelial cells. ACE plays an essential role in two physiological systems, one leading to the production of angiotensin II and the other to the degradation of bradykinin. The human ACE gene is located on chromosome 17q23, where an insertion/deletion polymorphism (I/D, rs ) in intron 16 has been identified. 2 This polymorphism is based on the presence (insertion, I) or absence (deletion, D) of a 287-bp nonsense DNA fragment. The DD genotype is associated with increased ACE levels, leading in turn to increased angiotensin II and bradykinin levels. Several investigators have investigated the association between ACE I/D polymorphism and AA risk, 3 12 but the results have been conflicting and inconclusive. This may possibly be partly because of the small sample size in each of the published studies, and different populations. To derive a more precise conclusion, we performed a meta-analysis of all eligible studies. This is, to our knowledge, the first genetic metaanalysis conducted with respect to the association between the ACE I/D polymorphism and AA risk. 1 Department of vascular surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Corresponding author: Yan Song, Department of vascular surgery, The First Affiliated Hospital of Zhengzhou University, 40 Daxue Road, Zhengzhou , Henan Province, China. songyanzhengzhou@126.com Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (

2 1126 Journal of the Renin-Angiotensin-Aldosterone System 16(4) Methods Publication search We searched all published studies (up to March 2014) in the PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) databases. The following keywords were used for searching: angiotensin-converting enzyme OR ACE AND polymorphism OR mutation OR variant OR variation OR genotype AND aortic aneurysm OR abdominal aortic aneurysm OR thoracic aortic aneurysm. We also perused the reference lists of the selected research papers and reviews to identify additional relevant studies. No language restrictions were imposed. Inclusion and exclusion criteria The inclusion criteria for identified articles were as follows: (1) studies on the relationship between ACE I/D polymorphism and AA risk; (2) case-control studies; (3) studies with full text articles; (4) sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI). Studies were excluded if one of the following existed: (1) not relevant to AA or ACE; (2) not designed as casecontrol studies; (3) genotype frequencies or number not offered; (4) animal studies; (5) editorials, reviews and abstracts; and (6) overlapping studies. Data extraction Data were extracted independently from each study that qualified: first author, publication date, population ethnicity, disease type, blood pressure, sample size, genotype numbers of cases and controls. Statistical analysis The strength of the association between ACE I/D polymorphism and AA risk was measured by OR and 95% CI. The random-effects model was used. Since most of the studies reported the association between ACE I/D polymorphism and AA risk in a recessive genetic model, this genetic model was also used in this meta-analysis. The statistical significance of summary OR was determined with Z test. Between-study heterogeneity was assessed by Chi-square test, and was quantified using the I 2 statistic (ranging from 0 to 100%), which was defined as the percentage of the observed between-study variability that is due to heterogeneity rather than chance. Subgroup analyses by ethnicity, disease type, and blood pressure were performed. To assess the stability of the meta-analysis, one-way sensitivity analysis was carried out. Publication bias was assessed by visual inspection of funnel plots, in which the standard error of log (OR) of each study was plotted against its log (OR). The Egger s test was used to assess publication bias statistically. 13 All statistical tests were performed by using STATA 12.0 software (Stata Corporation, College Station, TX). A p-value of <0.05 was considered significant. All the p-values were two-sided. Results Study characteristics Ten studies were selected for this meta-analysis One study was in Asians and nine studies were in Caucasians. Nine studies assessed the association between abdominal aortic aneurysm (AAA) and ACE I/D polymorphism, while three studies investigated the association between thoracic aortic aneurysm (TAA) and ACE I/D polymorphism. Blood pressure data could be extracted from three studies. The characteristics of these studies are shown in Table 1. Quantitative data synthesis The association between ACE I/D polymorphism and AA risk was investigated in 10 case-control studies with a total of 3557 cases and 5231 controls. The DD genotype of ACE was associated with a significantly increased risk of AA when compared with DI and II genotypes (OR=1.30; 95%CI, ; p<0.01; I 2 =68%; Figure 1). When stratified by ethnicity, a significantly elevated risk was observed in Caucasians (OR=1.31; 95%CI, ; p<0.01; I 2 =71%). A significantly increased AAA risk was observed (OR=1.29; 95%CI, ; p=0.02; I 2 =73%). However, ACE I/D polymorphism was not associated with TAA risk (OR=1.33; 95%CI, ; p=0.21; I 2 =52%). Subgroup analysis on blood pressure status showed that an increased risk was found in hypertensive patients (OR=1.52; 95%CI, ; p=0.04; I 2 =0%) but not in normotensive subjects (OR=1.46; 95%CI, ; p=0.30; I 2 =25%). Results of meta-analysis are listed in Table 2. A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set on the pooled ORs, and the corresponding pooled ORs were not materially altered (Figure 2). Publication bias was assessed by funnel plot. The shape of the funnel plot was symmetric (Figure 3). Furthermore, no significant publication bias was detected by Egger s test (p=0.07). Discussion This meta-analysis determined the associations between ACE I/D polymorphism and AA risk. We found that the ACE DD genotype was significantly associated with AA risk. In the subgroup analysis, we found that ACE DD carriers had increased AA risk among Caucasians but not Asians, suggesting a possible influence among environmental exposures and different genetic backgrounds; however, there was

3 Song et al Table 1. Studies and data included in this meta-analysis. Study/year Ethnicity Type Blood Case Control Case genotype Control genotype pressure DD DI II DD DI II Hamano/1999 Asian AAA Mixed Pola/2001 Caucasian AAA Mixed* Fatini/2005 Caucasian AAA Mixed* Jones 1/2008 Caucasian AAA Mixed Jones 2/2008 Caucasian AAA Mixed Jones 3/2008 Caucasian AAA Mixed Korcz/2009 Caucasian AAA Mixed* Lucarini/2009 Caucasian AAA Mixed Obukofe/2010 Caucasian AAA Mixed Lesauskaite/2011 Caucasian TAA Mixed Foffa/2012 Caucasian TAA Mixed Pisano/2012 Caucasian TAA Mixed *It was possible to extract data for hypertensive and normotensive patients separately. AAA, abdominal aortic aneurysm; TAA, thoracic aortic aneurysm. Figure 1. Meta-analysis of the association between the ACE I/D polymorphism and AA risk. only one study conducted in Asians. Therefore, a positive association between this polymorphism and AA risk in Asians could not be excluded. We also found that ACE I/D polymorphism was significantly associated with AAA risk. This result indicated that ACE I/D polymorphism might play a role in the development of AAA. In the TAA subgroup, however, we did not detect a significant association. When subgroup analysis was performed according to blood pressure status, a significant association was demonstrated in hypertensive patients. This result suggested that blood pressure status changed the role of ACE I/D polymorphism on AA. Evidence from both animal and human studies suggests that the renin angiotensin system (RAS) may play an important role in the formation and progression of AA. The most direct verification of a role of the RAS in AAAs

4 1128 Journal of the Renin-Angiotensin-Aldosterone System 16(4) Table 2. Results of meta-analysis. Test of association Heterogeneity OR (95% CI) p-value I 2 (%) p-value Overall 1.30 ( ) < <0.01 Asian 1.12 ( ) 0.70 NA NA Caucasian 1.31 ( ) < <0.01 AAA 1.29 ( ) <0.01 TAA 1.33 ( ) Hypertension 1.52 ( ) Normotension 1.46 ( ) AAA, abdominal aortic aneurysm; TAA, thoracic aortic aneurysm; NA, not available. Figure 2. Sensitivity analysis for ACE I/D polymorphism and AA risk. was the consistent demonstration of aneurysm formation induced by subcutaneous infusion of AngII into normal or obese mice. 14,15 Infusion of AngII also promotes pathologies that are localized to the thoracic aorta, predominantly in the ascending portion. This was first detected during AngII infusion into normal C57BL/6 mice. 16 Dissections of the ascending aorta occurred within 6 10 days after initiating AngII infusion. Retrospective analysis has demonstrated potential benefits of ACE inhibition in preventing aortic rupture. 17 In addition, administration of AT1 receptor antagonists was associated with reduced aortic expansion. 18 Since ACE is a key zinc metallopeptidase which catalyzes the conversion of angiotensin I to angiotensin II, ACE I/D polymorphism might play a critical role in AA. Significant heterogeneity existed in this meta-analysis. Subgroup analysis was used to find the sources of heterogeneity. We found that the I 2 value was decreased in the subgroup analysis by blood pressure. This result suggested that blood pressure status may be the major source of the heterogeneity. Results from the sensitivity analysis suggested stability of these results. In addition, funnel plots and Egger s tests did not find potential publication bias. There were some limitations in this meta-analysis. First, our results were based on unadjusted OR estimates, because not all published studies presented adjusted ORs or when they did, the ORs were not adjusted by the same potential confounders, such as age, sex and exposure variables. Thus, more comprehensive individual datasets are needed to allow for the adjustment by some co-variants and further evaluation of potential gene environment interactions for susceptibility to AA. Second, the included studies were carried out in Asians and Caucasians. Absence of data from other ethnic populations meant that a more comprehensive evaluation of the association between ACE I/D polymorphism and susceptibility to AA was not possible. Third, although we have tested for publication bias,

5 Song et al Figure 3. Funnel plot for ACE I/D polymorphism and AA risk. publication bias cannot be entirely excluded from a retrospective meta-analysis, despite our extensive search in different databases. In conclusion, this meta-analysis detected a significant association between ACE I/D polymorphism and risk of AA, especially in Caucasians. Conflicts of interest None declared. Funding This research was supported by Science and Technology Development Plan Project of Department of Science & Technology of Henan Province ( ). References 1. Golledge J and Kuivaniemi H. Genetics of abdominal aortic aneurysm. Curr Opin Cardiol 2013; 28: Sayed-Tabatabaei FA, Oostra BA, Isaacs A, et al. ACE polymorphisms. Circ Res 2006; 98: Hamano K, Ohishi M, Ueda M, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is not a risk factor predisposing to abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 1999; 18: Pola R, Gaetani E, Santoliquido A, et al. Abdominal aortic aneurysm in normotensive patients: Association with angiotensin-converting enzyme gene polymorphism. Eur J Vasc Endovasc Surg 2001; 21: Fatini C, Pratesi G, Sofi F, et al. ACE DD genotype: a predisposing factor for abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 2005; 29: Jones GT, Thompson AR, van Bockxmeer FM, et al. Angiotensin II type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts. Arterioscler Thromb Vasc Biol 2008; 28: Korcz A, Mikołajczyk-Stecyna J, Gabriel M, et al. Angiotensin-converting enzyme (ACE, I/D) gene polymorphism and susceptibility to abdominal aortic aneurysm or aortoiliac occlusive disease. J Surg Res ; 153: Lucarini L, Sticchi E, Sofi F, et al. ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm. Atherosclerosis 2009; 202: Obukofe B, Sayers RD, Thompson J, et al. Is there an association between angiotensin converting enzyme (ACE) genotypes and abdominal aortic aneurysm? Eur J Vasc Endovasc Surg 2010; 40: Lesauskaite V, Sinkunaite-Marsalkiene G, Tamosiunas A, et al. Protective effects of angiotensin-converting enzyme I/I and matrix metalloproteinase-3 6A/6A polymorphisms on dilatative pathology within the ascending thoracic aorta. Eur J Cardiothorac Surg 2011; 40: Foffa I, Murzi M, Mariani M, et al. Angiotensin-converting enzyme insertion/deletion polymorphism is a risk factor for thoracic aortic aneurysm in patients with bicuspid or tricuspid aortic valves. J Thorac Cardiovasc Surg 2012; 144: Pisano C, Maresi E, Balistreri CR, et al. Histological and genetic studies in patients with bicuspid aortic valve and ascending aorta complications. Interact Cardiovasc Thorac Surg 2012; 14: Balistreri CR, Pisano C, Candore G, et al. Focus on the unique mechanisms involved in thoracic aortic aneurysm formation in bicuspid aortic valve versus tricuspid aortic valve patients: Clinical implications of a pilot study. Eur J Cardiothorac Surg 2013; 43: e180 e Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: Deng GG, Martin-McNulty B, Sukovich DA, et al. Urokinase-type plasminogen activator plays a critical role in angiotensin II-induced abdominal aortic aneurysm. Circ Res 2003; 92: Uchida HA, Poduri A, Subramanian V, et al. Urokinase-type plasminogen activator deficiency in bone marrow-derived cells augments rupture of angiotensin II-induced abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2011; 31: Tieu BC, Lee C, Sun H, et al. An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest 2009; 119: Hackam DG, Thiruchelvam D and Redelmeier DA. Angiotensin-converting enzyme inhibitors and aortic rupture: A populationbased case-control study. Lancet 2006; 368: Thompson AR, Drenos F, Hafez H, et al. Candidate gene association studies in abdominal aortic aneurysm disease: A review and meta-analysis. Eur J Vasc Endovasc Surg 2008; 35: