Association between eNOS Gene a/b Polymorphism and Diabetic Retinopathy Susceptibility: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 ZENGZheng-hong , ZHONGLi , WANGMin , LEIChun-li

、Department of Endocrinology Medicine, The First Peoples' Hospital of Longquanyi District, Chengdu 610100, China;

Corresponding author：

Keywords：

eNOS; Diabetic retinopathy; Polymorphism; Systematic review; Meta-analysis; Case-control study

DOI：

10.7507/1672-2531.20150152

Video：

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Objective To systematically evaluate the association between eNOS gene a/b polymorphism and diabetic retinopathy susceptibility. Methods PubMed, EMbase, The Cochrane Library (Issue 5, 2015), CBM, CNKI, VIP and WanFang Data were systemically searched from inception to May 2015, to collect case-control studies about the eNOS a/b polymorphism and diabetic retinopathy susceptibility. Two reviewers independently screened literature, extracted data and evaluated the risk bias of included studies. Then, meta-analysis was performed by RevMan 5.2 software. Results A total of 16 case-control studies were included, which involved 3 232 diabetic retinopathy cases and 3 555 controls. The results of meta-analysis showed that, in the total analysis, the a/b polymorphism of the eNOS gene was not associated with diabetic retinopathy risk (dominant model:OR=0.94, 95%CI 0.78 to 1.15, P=0.57; recessive model:OR=0.97, 95%CI 0.78 to 1.22, P=0.88; aa vs. bb:OR=0.89, 95%CI 0.71 to 1.12, P=0.32; ab vs. bb:OR=0. 94, 95%CI 0.77 to 1.14, P=0.52; a vs. b:OR=0.97, 95%CI 0.82 to 1.14, P=0.70); In the subgroup analysis by ethnicity, the a/b polymorphism was significantly associated with the risk of diabetic retinopathy in Africans, but not in Asians and Caucasians. Conclusion The a/b polymorphism in the eNOS gene may be a risk factor of diabetic retinopathy in Africans.

Citation： ZENGZheng-hong, ZHONGLi, WANGMin, LEIChun-li. Association between eNOS Gene a/b Polymorphism and Diabetic Retinopathy Susceptibility: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2015, 15(8): 898-906. doi: 10.7507/1672-2531.20150152 Copy

1.	Hsieh YY, Huang YC, Chang CC, et al. Chromosome 15q21-22-related polymorphisms and haplotypes are associated with susceptibility to type-2 diabetic nonproliferative retinopathy. Genet Test Mol Biomarkers, 2012, 16(5):442-448.
2.	Lu Y, Ge Y, Hu Q, et al. Association between angiotensin-converting enzyme gene polymorphism and diabetic retinopathy in the Chinese population. J Renin Angiotensin Aldosterone Syst, 2012, 13(2):289-295.
3.	Paine SK, Sen A, Choudhuri S, et al. Association of tumor necrosis factor alpha, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjects. Retina, 2012, 32(6):1197-1203.
4.	Okumus S, Igci YZ, Taskin T, et al. Association between Thr21Met and Ser89Asn polymorphisms of the urotensin-Ⅱ (UTS2) gene, diabetes mellitus, and diabetic retinopathy. Curr Eye Res, 2012, 37(10):921-929.
5.	Hu C, Zhang R, Yu W, et al. CPVL/CHN2 genetic variant is associated with diabetic retinopathy in Chinese type 2 diabetic patients. Diabetes, 2011, 60(11):3085-3089.
6.	Niu W, Qi Y. An updated meta-analysis of methylenetetrahydrofolate reductase gene 677C/T polymorphism with diabetic nephropathy and diabetic retinopathy. Diabetes Res Clin Pract, 2012, 95(1):110-118.
7.	Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc Ophthalmol, 2012, 124(1):15-26.
8.	Kang P, Tian C, Jia C. Association of RAGE gene polymorphisms with type 2 diabetes mellitus, diabetic retinopathy and diabetic nephropathy. Gene, 2012, 500(1):1-9.
9.	de Syllos RW, Sandrim VC, Lisboa HR, et al. Endothelial nitric oxide synthase genotype and haplotype are not associated with diabetic retinopathy in diabetes type 2 patients. Nitric Oxide, 2006, 15(4):417-422.
10.	Santos KG, Crispim D, Canani LH, et al. Relationship of endothelial nitric oxide synthase (eNOS) gene polymorphisms with diabetic retinopathy in Caucasians with type 2 diabetes. Ophthalmic Genet, 2012, 33(1):23-27.
11.	孙海燕, 杨明功, 刘树琴, 等. 内皮型一氧化氮合酶基因多态性与 2 型糖尿病及视网膜病变. 中华内分泌代谢杂志, 2004, 20(1):52-53.
12.	张敏, 刘华, 徐玉善, 等. 2型糖尿病患者eNOS基因第4内含子的多态性与糖尿病视网膜病相关性. 中华内分泌代谢杂志, 2005, 21(2):146-147.
13.	岳枚, 喻晓兵, 戴虹, 等. 内皮型一氧化氮合酶基因第4内含子中27碱基对重复序列多态性与糖尿病视网膜病变的相关性研究. 中华眼底病杂志, 2011, 27(3):214-217.
14.	Cheema BS, kohli HS, Sharma R, et al. Endothelial nitric oxide synthase gene polymorphism and type 2 diabetic retinopathy among Asian Indians. Acta Diabetol, 2012, 49(6):481-488.
15.	Ezzidi I, Mtiraoui N, Mohamed MB, et al. Endothelial nitric oxide synthase Glu298Asp, 4b/a, and T-786C polymorphisms in type 2 diabetic retinopathy. Clin Endocrinol (Oxf), 2008, 68(4):542-546.
16.	Awata T, Neda T, Iizuka H, et al. Endothelial nitric oxide synthase gene is associated with diabetic macular edema in type 2 diabetes. Diabetes Care, 2004, 27(9):2184-2190.
17.	Mehrab-Mohseni M, Tabatabaei-Malazy O, Hasani-Ranjbar S, et al. Endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism association with type 2 diabetes and its chronic complications. Diabetes Res Clin Pract, 2011, 91(3):348-352.
18.	Petrovic MG, Cilensek I, Petrovic D. Manganese superoxide dismutase gene polymorphism (V16A) is associated with diabetic retinopathy in Slovene (Caucasians) type 2 diabetes patients. Dis Markers, 2008, 24(1):59-64.
19.	Cilensek I, Mankoc S, Globocnik Petrovic M, et al. The 4a/4a genotype of the VNTR polymorphism for endothelial nitric oxide synthase (eNOS) gene predicts risk for proliferative diabetic retinopathy in Slovenian patients (Caucasians) with type 2 diabetes mellitus. Mol Biol Rep, 2012, 39(6):7061-7067.
20.	Chen Y, Huang H, Zhou J, et al. Polymorphism of the endothelial nitric oxide synthase gene is associated with diabetic retinopathy in a cohort of West Africans. Mol Vis, 2007, 13:2142-2147.
21.	Suganthalakshmi B, Anand R, Kim R, et al. Association of VEGF and eNOS gene polymorphisms in type 2 diabetic retinopathy. Mol Vis, 2006, 12:336-341.
22.	Narne P, Ponnaluri KC, Siraj M, et al. Association Analysis of Polymorphisms in Genes Related to Oxidative Stress in South Indian Type 2 Diabetic Patients with Retinopathy. Ophthalmic Genet, 2014:in press.
23.	佘重阳, 杨秀芬, 顾虹, 等. 内皮型一氧化氮合酶基因内含子的数目可变串联重复多态性与糖尿病视网膜病变的相关性研究. 中华眼科杂志, 2015, 51(5):338-343.
24.	Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9):603-605.
25.	陈甲, 和儒林, 朗莹, 等. 中国人群MTHFR基因C677T多态性与青中年缺血性脑卒中相关性的Meta分析. 中国循证医学杂志, 2014, 14(4):435-442.
26.	Qian-Qian Y, Yong Y, Jing Z, et al. Association between a 27-bp variable number of tandem repeat polymorphism in intron 4 of the eNOS gene and risk for diabetic retinopathy Type 2 diabetes mellitus:a meta-analysis. Curr Eye Res, 2014, 39(10):1052-1058.

1. Hsieh YY, Huang YC, Chang CC, et al. Chromosome 15q21-22-related polymorphisms and haplotypes are associated with susceptibility to type-2 diabetic nonproliferative retinopathy. Genet Test Mol Biomarkers, 2012, 16(5):442-448.
2. Lu Y, Ge Y, Hu Q, et al. Association between angiotensin-converting enzyme gene polymorphism and diabetic retinopathy in the Chinese population. J Renin Angiotensin Aldosterone Syst, 2012, 13(2):289-295.
3. Paine SK, Sen A, Choudhuri S, et al. Association of tumor necrosis factor alpha, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjects. Retina, 2012, 32(6):1197-1203.
4. Okumus S, Igci YZ, Taskin T, et al. Association between Thr21Met and Ser89Asn polymorphisms of the urotensin-Ⅱ (UTS2) gene, diabetes mellitus, and diabetic retinopathy. Curr Eye Res, 2012, 37(10):921-929.
5. Hu C, Zhang R, Yu W, et al. CPVL/CHN2 genetic variant is associated with diabetic retinopathy in Chinese type 2 diabetic patients. Diabetes, 2011, 60(11):3085-3089.
6. Niu W, Qi Y. An updated meta-analysis of methylenetetrahydrofolate reductase gene 677C/T polymorphism with diabetic nephropathy and diabetic retinopathy. Diabetes Res Clin Pract, 2012, 95(1):110-118.
7. Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc Ophthalmol, 2012, 124(1):15-26.
8. Kang P, Tian C, Jia C. Association of RAGE gene polymorphisms with type 2 diabetes mellitus, diabetic retinopathy and diabetic nephropathy. Gene, 2012, 500(1):1-9.
9. de Syllos RW, Sandrim VC, Lisboa HR, et al. Endothelial nitric oxide synthase genotype and haplotype are not associated with diabetic retinopathy in diabetes type 2 patients. Nitric Oxide, 2006, 15(4):417-422.
10. Santos KG, Crispim D, Canani LH, et al. Relationship of endothelial nitric oxide synthase (eNOS) gene polymorphisms with diabetic retinopathy in Caucasians with type 2 diabetes. Ophthalmic Genet, 2012, 33(1):23-27.
11. 孙海燕, 杨明功, 刘树琴, 等. 内皮型一氧化氮合酶基因多态性与 2 型糖尿病及视网膜病变. 中华内分泌代谢杂志, 2004, 20(1):52-53.
12. 张敏, 刘华, 徐玉善, 等. 2型糖尿病患者eNOS基因第4内含子的多态性与糖尿病视网膜病相关性. 中华内分泌代谢杂志, 2005, 21(2):146-147.
13. 岳枚, 喻晓兵, 戴虹, 等. 内皮型一氧化氮合酶基因第4内含子中27碱基对重复序列多态性与糖尿病视网膜病变的相关性研究. 中华眼底病杂志, 2011, 27(3):214-217.
14. Cheema BS, kohli HS, Sharma R, et al. Endothelial nitric oxide synthase gene polymorphism and type 2 diabetic retinopathy among Asian Indians. Acta Diabetol, 2012, 49(6):481-488.
15. Ezzidi I, Mtiraoui N, Mohamed MB, et al. Endothelial nitric oxide synthase Glu298Asp, 4b/a, and T-786C polymorphisms in type 2 diabetic retinopathy. Clin Endocrinol (Oxf), 2008, 68(4):542-546.
16. Awata T, Neda T, Iizuka H, et al. Endothelial nitric oxide synthase gene is associated with diabetic macular edema in type 2 diabetes. Diabetes Care, 2004, 27(9):2184-2190.
17. Mehrab-Mohseni M, Tabatabaei-Malazy O, Hasani-Ranjbar S, et al. Endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism association with type 2 diabetes and its chronic complications. Diabetes Res Clin Pract, 2011, 91(3):348-352.
18. Petrovic MG, Cilensek I, Petrovic D. Manganese superoxide dismutase gene polymorphism (V16A) is associated with diabetic retinopathy in Slovene (Caucasians) type 2 diabetes patients. Dis Markers, 2008, 24(1):59-64.
19. Cilensek I, Mankoc S, Globocnik Petrovic M, et al. The 4a/4a genotype of the VNTR polymorphism for endothelial nitric oxide synthase (eNOS) gene predicts risk for proliferative diabetic retinopathy in Slovenian patients (Caucasians) with type 2 diabetes mellitus. Mol Biol Rep, 2012, 39(6):7061-7067.
20. Chen Y, Huang H, Zhou J, et al. Polymorphism of the endothelial nitric oxide synthase gene is associated with diabetic retinopathy in a cohort of West Africans. Mol Vis, 2007, 13:2142-2147.
21. Suganthalakshmi B, Anand R, Kim R, et al. Association of VEGF and eNOS gene polymorphisms in type 2 diabetic retinopathy. Mol Vis, 2006, 12:336-341.
22. Narne P, Ponnaluri KC, Siraj M, et al. Association Analysis of Polymorphisms in Genes Related to Oxidative Stress in South Indian Type 2 Diabetic Patients with Retinopathy. Ophthalmic Genet, 2014:in press.
23. 佘重阳, 杨秀芬, 顾虹, 等. 内皮型一氧化氮合酶基因内含子的数目可变串联重复多态性与糖尿病视网膜病变的相关性研究. 中华眼科杂志, 2015, 51(5):338-343.
24. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9):603-605.
25. 陈甲, 和儒林, 朗莹, 等. 中国人群MTHFR基因C677T多态性与青中年缺血性脑卒中相关性的Meta分析. 中国循证医学杂志, 2014, 14(4):435-442.
26. Qian-Qian Y, Yong Y, Jing Z, et al. Association between a 27-bp variable number of tandem repeat polymorphism in intron 4 of the eNOS gene and risk for diabetic retinopathy Type 2 diabetes mellitus:a meta-analysis. Curr Eye Res, 2014, 39(10):1052-1058.

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Association between eNOS Gene a/b Polymorphism and Diabetic Retinopathy Susceptibility: A Meta-analysis

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