血管紧张素转换酶基因多态性与主动脉瘤易感性的荟萃分析
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摘要
目的通过荟萃分析探讨血管紧张素转换酶(ACE)基因插入/缺失(I/D)多态性与主动脉瘤易感性的关系。方法计算机检索Cochrane Library、Elsevier ScienceDirect、PubMed/Medline、万方数据知识服务平台、中国知网、维普期刊资源整合服务平台,搜索已发表的关于ACE基因多态性与主动脉瘤的病例对照研究,检索时限为建库至2018-08-01。按Cochrane系统评价方法筛选文献、提取资料并评价质量后,采用Stata 15软件进行荟萃分析。结果最终纳入17篇文献,其中病例组4597例,对照组6407例。荟萃分析结果显示,ACE基因I/D多态性与主动脉瘤发病存在相关性。等位基因分析显示,ACE基因I/D多态性与主动脉瘤发病相关(OR=1.41,95%CI 1.21～1.65,P<0.001),亚组分析中,亚洲人亚组OR=1.69 (95%CI 1.18～2.41,P=0.004),高加索人亚组OR=1.34(95%CI 1.14～1.56,P<0.001);腹主动脉瘤亚组OR=1.25(95%CI 1.06～1.49,P=0.01),胸主动脉瘤亚组OR=1.59(95%CI 1.10～2.29,P=0.014),主动脉瘤亚组OR=2.03(95%CI 1.66～2.48,P<0.001),主动脉夹层亚组OR=1.70(95%CI 1.18～2.45,P=0.004)。隐性基因模型(II+DI比DD)分析显示,ACE基因I/D多态性与主动脉瘤发病相关(OR=1.55,95%CI 1.20～2.01,P=0.001),在隐性模型亚组分析中,亚洲人亚组OR=2.44(95%CI 1.39～4.29,P=0.002),高加索人亚组OR=1.34(95%CI 1.05～1.69,P=0.017);腹主动脉瘤亚组OR=1.31(95%CI 0.99～1.73,P=0.058),胸主动脉瘤亚组OR=1.33(95%CI 0.85～2.07,P=0.206),主动脉瘤亚组OR=3.72(95%CI 2.75～5.03,P<0.001),主动脉夹层亚组OR=2.13(95%CI 1.22～3.71,P=0.008)。显性模型(DD+DI比II)分析显示,ACE基因I/D多态性与主动脉瘤发病相关(OR=1.52,95%CI 1.28～1.81,P<0.001),在显性模型亚组分析中,亚洲人亚组OR=1.39(95%CI 0.97～1.99,P=0.07),高加索人亚组OR=1.57(95%CI 1.28～1.94,P<0.001);腹主动脉瘤亚组OR=1.35(95%CI 1.10～1.65,P=0.005),胸主动脉瘤亚组OR=2.42(95%CI 1.70～3.46,P<0.001),主动脉瘤亚组OR=1.29(95%CI 0.94～1.79,P=0.119),主动脉夹层亚组OR=1.72(95%CI 1.31～2.28,P<0.001)。结论总体上ACE基因I/D多态性与主动脉瘤发病存在相关性,为主动脉瘤的发病危险因素。在隐性模型胸主动脉瘤亚组和腹主动脉瘤亚组,显性模型亚洲人亚组、主动脉瘤亚组中,ACE基因I/D多态性与主动脉瘤相关性无统计学意义,还需要进一步研究验证。
Objective To explore the association between angiotensin converting enzyme(ACE) polymorphism and aortic aneurysm(AA) risk by meta-analysis. Methods The Cochrane Library, Elsevier ScienceDirect, PubMed/Medline, Wanfang data, CNKI and CQVIP were used to identify case-control studies on ACE gene polymorphism and AA published from database building to August 1 th, 2018. After screening literature, extracting data and evaluating quality according to Cochrane system evaluation method, meta-analysis was carried out with Stata 15 software. Results Finally, 17 articles were included, involving 4597 cases and 6407 controls. Meta-analysis showed a significant association between ACE I/D polymorphism and aortic aneurysm risk. In allele model(OR=1.41, 95% CI 1.21-1.65, P<0.001), statistically significant associations were found in Asian and Caucasian subgroups in subgroup analysis by ethnicity(OR=1.69, 95% CI 1.18-2.41, P=0.004; OR=1.34, 95% CI 1.14-1.56, P<0.001, respectively), and also in abdominal aortic aneurysm(AAA), thoracic aortic aneurysm(TAA), AA and aortic dissection(AD) subgroups in subgroup analysis by disease(OR=1.25, 95% CI 1.06-1.49, P=0.01; OR=1.59, 95% CI 1.10-2.29, P=0.014; OR=2.03, 95% CI 1.66-2.48, P<0.001; OR=1.70, 95% CI 1.18-2.45, P=0.004, respectively). In recessive model(OR=1.55, 95% CI 1.20-2.01, P=0.001), statistically significant associations were found in Asian and Caucasian subgroups in subgroup analysis by ethnicity(OR=2.44, 95% CI 1.39-4.29, P=0.002; OR=1.34, 95% CI 1.05-1.69, P=0.017, respectively), and in AAA, TAA, AA and AD subgroups in subgroup analysis by disease(OR=1.31, 95% CI 0.99-1.73, P=0.058; OR=1.33, 95% CI 0.85-2.07, P=0.206; OR=3.72, 95% CI 2.75-5.03, P<0.001; OR=2.13, 95%CI 1.22-3.71, P=0.008, respectively). In dominant model(OR=1.52, 95% CI 1.28-1.81, P<0.001), OR of Asian and Caucasian subgroup in subgroup analysis by ethnicity was 1.39(95% CI 0.97-1.99, P=0.07) and 1.57(95% CI 1.28-1.94, P<0.001), respectively. In the subgroup analysis by disease, OR of AAA, TAA, AA and AD subgroup was 1.35(95% CI 1.10-1.65, P=0.005), 2.42(95% CI 1.70-3.46, P<0.001), 1.29(95% CI 0.94-1.79, P=0.119) and 1.72(95% CI 1.31-2.28, P<0.001), respectively. Conclusion ACE I/D polymorphism is generally associated with the incidence of aortic aneurysms, and a risk factor for the occurrence of aortic aneurysms. In recessive model of thoracic aortic aneurysm subgroup and abdominal aortic aneurysm subgroup, dominant model of Asian subgroup and aortic aneurysm subgroup, there are no significant correlation between ACE gene I/D polymorphism and aortic aneurysm, and further research is needed.
Objective To explore the association between angiotensin converting enzyme(ACE) polymorphism and aortic aneurysm(AA) risk by meta-analysis. Methods The Cochrane Library, Elsevier ScienceDirect, PubMed/Medline, Wanfang data, CNKI and CQVIP were used to identify case-control studies on ACE gene polymorphism and AA published from database building to August 1 th, 2018. After screening literature, extracting data and evaluating quality according to Cochrane system evaluation method, meta-analysis was carried out with Stata 15 software. Results Finally, 17 articles were included, involving 4597 cases and 6407 controls. Meta-analysis showed a significant association between ACE I/D polymorphism and aortic aneurysm risk. In allele model(OR=1.41, 95% CI 1.21-1.65, P<0.001), statistically significant associations were found in Asian and Caucasian subgroups in subgroup analysis by ethnicity(OR=1.69, 95% CI 1.18-2.41, P=0.004; OR=1.34, 95% CI 1.14-1.56, P<0.001, respectively), and also in abdominal aortic aneurysm(AAA), thoracic aortic aneurysm(TAA), AA and aortic dissection(AD) subgroups in subgroup analysis by disease(OR=1.25, 95% CI 1.06-1.49, P=0.01; OR=1.59, 95% CI 1.10-2.29, P=0.014; OR=2.03, 95% CI 1.66-2.48, P<0.001; OR=1.70, 95% CI 1.18-2.45, P=0.004, respectively). In recessive model(OR=1.55, 95% CI 1.20-2.01, P=0.001), statistically significant associations were found in Asian and Caucasian subgroups in subgroup analysis by ethnicity(OR=2.44, 95% CI 1.39-4.29, P=0.002; OR=1.34, 95% CI 1.05-1.69, P=0.017, respectively), and in AAA, TAA, AA and AD subgroups in subgroup analysis by disease(OR=1.31, 95% CI 0.99-1.73, P=0.058; OR=1.33, 95% CI 0.85-2.07, P=0.206; OR=3.72, 95% CI 2.75-5.03, P<0.001; OR=2.13, 95%CI 1.22-3.71, P=0.008, respectively). In dominant model(OR=1.52, 95% CI 1.28-1.81, P<0.001), OR of Asian and Caucasian subgroup in subgroup analysis by ethnicity was 1.39(95% CI 0.97-1.99, P=0.07) and 1.57(95% CI 1.28-1.94, P<0.001), respectively. In the subgroup analysis by disease, OR of AAA, TAA, AA and AD subgroup was 1.35(95% CI 1.10-1.65, P=0.005), 2.42(95% CI 1.70-3.46, P<0.001), 1.29(95% CI 0.94-1.79, P=0.119) and 1.72(95% CI 1.31-2.28, P<0.001), respectively. Conclusion ACE I/D polymorphism is generally associated with the incidence of aortic aneurysms, and a risk factor for the occurrence of aortic aneurysms. In recessive model of thoracic aortic aneurysm subgroup and abdominal aortic aneurysm subgroup, dominant model of Asian subgroup and aortic aneurysm subgroup, there are no significant correlation between ACE gene I/D polymorphism and aortic aneurysm, and further research is needed.
引文
[1] Golledge J,Muller J,Daugherty A,et al.Abdominal aortic aneurysm:pathogenesis and implications for management[J].Arterioscler Thromb Vasc Biol,2006,26(12):2605-2613.
[2] Henrion D,Benessiano JL,Lévy BI.In vitro modulation of a resistance artery diameter by the tissue renin-angiotensin system of a large donor artery[J].Circ Res,1997,80(2):189.
[3] Kranzh?fer R,Schmidt J,Pfeiffer CA,et al.Angiotensin induces inflammatory activation of human vascular smooth muscle cells[J].Arterioscler Thromb Vasc Biol,1999,19(7):1623-1629.
[4] Heeneman S,Sluimer JC,Daemen MJAP.Angiotensin-converting enzyme and vascular remodeling[J].Circ Res,2007,101(5):441-454.
[5] Hackam DG,Thiruchelvam D,Redelmeier DA.Angiotensin-converting enzyme inhibitors and aortic rupture:a population-based case-control study[J].Lancet,2006,368(9536):659-665.
[6] Liao S,Miralles M,Kelley BJ,et al.Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors[J].J Vasc Surg,2001,33(5):1057-1064.
[7] Rigat B,Hubert C,Alhenc-Gelas F,et al.An insertion/deletion polymorphism in the angiotensin Ⅰ-converting enzyme gene accounting for half the variance of serum enzyme levels[J].J Clin Invest,1990,86(4):1343-1346.
[8] Antoniou GA,Lazarides MK,Patera S,et al.Assessment of insertion/deletion polymorphism of the angiotensin-converting enzyme gene in abdominalaortic aneurysm and inguinal hernia[J].Vascular,2013,21(1):1-5.
[9] Fatini C,Pratesi G,Sofi F,et al.ACE DD genotype:a predisposing factor for abdominal aortic aneurysm[J].Eur J Vasc Endovasc Surg,2005,29(3):227-232.
[10] 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].J Thorac Cardiovasc Surg,2012,144(2):390-395.
[11] 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[J].Eur J Vasc Endovasc Surg,1999,18(2):158-161.
[12] Jing Q,Wang X,Ma Y,et al.Angiotensin-converting enzyme I/D polymorphism and the risk of thoracic aortic dissection in Chinese Han population[J].Mol Biol Rep,2013,40(2):1249-1254.
[13] Jones G,Thompson A,van Bockxmeer F,et al.Angiotensin Ⅱ type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts[J].Arterioscler Thromb Vasc Biol,2008,28(4):764-770.
[14] Kalay N,Caglayan O,Akkaya H,et al.The deletion polymorphism of the angiotensin-converting enzyme gene is associated with acute aortic dissection[J].Tohoku J Exp Med,2009,219(1):33-37.
[15] Korcz A,Miko?ajczyk-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].J Surg Res,2009,153(1):76-82.
[16] Lesauskaite V,Sinkunaite-Marsalkiene G,Tamosiunas A,et al.Protectiveeffects of angiotensin-converting enzyme I/I and matrix metalloproteinase-3 6A/6A polymorphisms on dilatative pathology within the ascending thoracic aorta[J].Eur J Cardiothorac Surg,2011,40(1):23-27.
[17] Lucarini L,Sticchi E,Sofi F,et al.ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm[J].Atherosclerosis,2009,202(1):205-210.
[18] Obukofe B,Sayers R,Thompson J,et al.Is there an association between angiotensin converting enzyme (ACE) genotypes and abdominal aortic aneurysm?[J].Eur J Vasc Endovasc Surg,2010,40(4):457-460.
[19] Pisano C,Maresi E,Balistreri C,et al.Histological and genetic studies in patients with bicuspid aortic valve and ascending aorta complications[J].Interact Cardiovasc Thorac Surg,2012,14(3):300-306.
[20] Pola R,Gaetani E,Santoliquido A,et al.Abdominal aortic aneurysm in normotensive patients:association with angiotensin-converting enzyme gene polymorphism[J].Eur J Vasc Endovasc Surg,2001,21(5):445-449.
[21] Tangurek B,Ketenci B,Ozay B,et al.Lack of association between angiotensin-converting enzyme gene polymorphism and type Ⅰ aortic dissection[J].J Int Med Res,2008,36(4):714-720.
[22] Crkvenac Gregorek A,Gornik K,Polancec D,et al.Association of 1166A>CATR,-1562C>T MMP-9,ACE I/D,and CCR5Δ32 polymorphisms with abdominal aortic aneurysm in croatian patients[J].Genet Test Mol Biomarkers,2016,20(10):616-623.
[23] Zhang Y,Huang H,Ma Y,et al.Association of the KLK1 rs5516 G allele and the ACE D allele with aortic aneurysm and atherosclerotic stenosis[J].Medicine (Baltimore),2016,95(44):e5120.
[24] 孙惠萍.急性主动脉夹层临床研究及与ACE基因I/D多态性的相关性研究[D].乌鲁木齐:新疆医科大学,2013.
[25] Bader M.Tissue renin-angiotensin-aldosterone systems:targets for pharmacological therapy[J].Annu Rev Pharmacol Toxicol,2010,50(1):439-465.
[26] Unger T.The role of the renin-angiotensin system in the development of cardiovascular disease[J].Am J Cardiol,2002,89(2):3-9.
[2] Henrion D,Benessiano JL,Lévy BI.In vitro modulation of a resistance artery diameter by the tissue renin-angiotensin system of a large donor artery[J].Circ Res,1997,80(2):189.
[3] Kranzh?fer R,Schmidt J,Pfeiffer CA,et al.Angiotensin induces inflammatory activation of human vascular smooth muscle cells[J].Arterioscler Thromb Vasc Biol,1999,19(7):1623-1629.
[4] Heeneman S,Sluimer JC,Daemen MJAP.Angiotensin-converting enzyme and vascular remodeling[J].Circ Res,2007,101(5):441-454.
[5] Hackam DG,Thiruchelvam D,Redelmeier DA.Angiotensin-converting enzyme inhibitors and aortic rupture:a population-based case-control study[J].Lancet,2006,368(9536):659-665.
[6] Liao S,Miralles M,Kelley BJ,et al.Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors[J].J Vasc Surg,2001,33(5):1057-1064.
[7] Rigat B,Hubert C,Alhenc-Gelas F,et al.An insertion/deletion polymorphism in the angiotensin Ⅰ-converting enzyme gene accounting for half the variance of serum enzyme levels[J].J Clin Invest,1990,86(4):1343-1346.
[8] Antoniou GA,Lazarides MK,Patera S,et al.Assessment of insertion/deletion polymorphism of the angiotensin-converting enzyme gene in abdominalaortic aneurysm and inguinal hernia[J].Vascular,2013,21(1):1-5.
[9] Fatini C,Pratesi G,Sofi F,et al.ACE DD genotype:a predisposing factor for abdominal aortic aneurysm[J].Eur J Vasc Endovasc Surg,2005,29(3):227-232.
[10] 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].J Thorac Cardiovasc Surg,2012,144(2):390-395.
[11] 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[J].Eur J Vasc Endovasc Surg,1999,18(2):158-161.
[12] Jing Q,Wang X,Ma Y,et al.Angiotensin-converting enzyme I/D polymorphism and the risk of thoracic aortic dissection in Chinese Han population[J].Mol Biol Rep,2013,40(2):1249-1254.
[13] Jones G,Thompson A,van Bockxmeer F,et al.Angiotensin Ⅱ type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts[J].Arterioscler Thromb Vasc Biol,2008,28(4):764-770.
[14] Kalay N,Caglayan O,Akkaya H,et al.The deletion polymorphism of the angiotensin-converting enzyme gene is associated with acute aortic dissection[J].Tohoku J Exp Med,2009,219(1):33-37.
[15] Korcz A,Miko?ajczyk-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].J Surg Res,2009,153(1):76-82.
[16] Lesauskaite V,Sinkunaite-Marsalkiene G,Tamosiunas A,et al.Protectiveeffects of angiotensin-converting enzyme I/I and matrix metalloproteinase-3 6A/6A polymorphisms on dilatative pathology within the ascending thoracic aorta[J].Eur J Cardiothorac Surg,2011,40(1):23-27.
[17] Lucarini L,Sticchi E,Sofi F,et al.ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm[J].Atherosclerosis,2009,202(1):205-210.
[18] Obukofe B,Sayers R,Thompson J,et al.Is there an association between angiotensin converting enzyme (ACE) genotypes and abdominal aortic aneurysm?[J].Eur J Vasc Endovasc Surg,2010,40(4):457-460.
[19] Pisano C,Maresi E,Balistreri C,et al.Histological and genetic studies in patients with bicuspid aortic valve and ascending aorta complications[J].Interact Cardiovasc Thorac Surg,2012,14(3):300-306.
[20] Pola R,Gaetani E,Santoliquido A,et al.Abdominal aortic aneurysm in normotensive patients:association with angiotensin-converting enzyme gene polymorphism[J].Eur J Vasc Endovasc Surg,2001,21(5):445-449.
[21] Tangurek B,Ketenci B,Ozay B,et al.Lack of association between angiotensin-converting enzyme gene polymorphism and type Ⅰ aortic dissection[J].J Int Med Res,2008,36(4):714-720.
[22] Crkvenac Gregorek A,Gornik K,Polancec D,et al.Association of 1166A>CATR,-1562C>T MMP-9,ACE I/D,and CCR5Δ32 polymorphisms with abdominal aortic aneurysm in croatian patients[J].Genet Test Mol Biomarkers,2016,20(10):616-623.
[23] Zhang Y,Huang H,Ma Y,et al.Association of the KLK1 rs5516 G allele and the ACE D allele with aortic aneurysm and atherosclerotic stenosis[J].Medicine (Baltimore),2016,95(44):e5120.
[24] 孙惠萍.急性主动脉夹层临床研究及与ACE基因I/D多态性的相关性研究[D].乌鲁木齐:新疆医科大学,2013.
[25] Bader M.Tissue renin-angiotensin-aldosterone systems:targets for pharmacological therapy[J].Annu Rev Pharmacol Toxicol,2010,50(1):439-465.
[26] Unger T.The role of the renin-angiotensin system in the development of cardiovascular disease[J].Am J Cardiol,2002,89(2):3-9.