Acta Diabetologica

, Volume 47, Supplement 1, pp 187–193 | Cite as

Angiotensin-converting enzyme gene polymorphism is associated with proliferative diabetic retinopathy: a meta-analysis

Original Article


The association of angiotensin-converting enzyme (ACE) gene polymorphism with diabetic retinopathy (DR) was investigated in many studies with conflicting results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating I (insert)/D (delete) polymorphism to the risk of developing DR was conducted. This meta-analysis included genotype data on 2,342 cases with DR and 2,048 controls free of DR. Summary odds ratios were estimated. Potential sources of heterogeneity and bias were explored. Overall, in allelic genetic model, heterogeneity between studies was nonsignificant (P = 0.12). No publication bias was observed in the regression asymmetry test (τ = 0.84, P = 0.41). There was no significant association between this variant and DR. In additional analysis, the association of I/D variant with retinopathy was nonsignificant both in patients with type 1 diabetes (T1D) (1.01 [95% CI: 0.79–1.29]) and in patients with type 2 diabetes (T2D) (1.12 [95% CI: 0.93–1.35]). Significant association was not also observed between I/D variant and the background diabetic retinopathy (BDR). For the I/D polymorphism and its relationship to proliferative diabetic retinopathy (PDR), the dominant model showed nonsignificant heterogeneity among studies (P = 0.52; I2 = 0%), and the fixed estimate pooled odd ratio (OR) JOPwas significant, at 1.37 [95% CI: 1.02–1.84]. No association was observed between ACE I/D variant and DR, irrespective of the diabetic type. There was moderate evidence of its relationship to PDR, while its relationship to BDR was not found. Studies exploring the association between ACE I/D polymorphism and BDR or PDR may help us better understand the genetics of DR.


ACE polymorphism Diabetes mellitus Retinopathy 



Type 1 diabetes


Type 2 diabetes


Background diabetic retinopathy


Proliferative diabetic retinopathy


Angiotensin-converting enzyme


  1. 1.
    Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, Schunkert H (1995) Angiotensin-converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 92:1387–1388PubMedGoogle Scholar
  2. 2.
    Globocnik-Petrovic M, Hawlina M, Peterlin B, Petrovic D (2003) Insertion/deletion plasminogen activator inhibitor 1 and insertion/deletion angiotensin-converting enzyme gene polymorphisms in diabetic retinopathy in type 2 diabetes. Ophthalmologica 217:219–224CrossRefPubMedGoogle Scholar
  3. 3.
    Fujisawa T, Ikegami H, Kawaguchi Y, Hamada Y, Ueda H, Shintani M, Fukuda M, Ogihara T (1998) Meta-analysis of association of insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy. Diabetologia 41:47–53CrossRefPubMedGoogle Scholar
  4. 4.
    Wiwanitkit V (2008) Angiotensin-converting enzyme gene polymorphism is correlated to diabetic retinopathy: a meta-analysis. J Diabetes Complicat 22:144–146CrossRefPubMedGoogle Scholar
  5. 5.
    Davey SG, Egger M (1997) Meta-analyses of randomised controlled trials. Lancet 350:1182Google Scholar
  6. 6.
    Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315:629–634Google Scholar
  7. 7.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101CrossRefPubMedGoogle Scholar
  8. 8.
    Tarnow L, Cambien F, Rossing P, Nielsen FS, Hansen BV, Lecerf L, Poirier O, Danilov S, Parving HH (1995) Lack of relationship between an insertion/deletion polymorphism in the angiotensin I-converting enzyme gene and diabetic nephropathy and proliferative retinopathy in IDDM patients. Diabetes 44(5):489–494CrossRefPubMedGoogle Scholar
  9. 9.
    Ringel J, Beige J, Kunz R, Distler A, Sharma AM (1997) Genetic variants of the renin-angiotensin system, diabetic nephropathy and hypertension. Diabetologia 440:193–199CrossRefGoogle Scholar
  10. 10.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558CrossRefPubMedGoogle Scholar
  11. 11.
    Fujisawa T, Ikegami H, Shen GQ, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Rakugi H, Higaki J (1995) Angiotensin I-converting enzyme gene polymorphism is associated with myocardial infarction, but not with retinopathy or nephropathy, in NIDDM. Diabetes Care 18:983–995CrossRefPubMedGoogle Scholar
  12. 12.
    Feghhi M, Nikzamir A, Esteghamati A, Farahi F, Nakhjavani M, Rashidi A (2008) The relationship between angiotensin-converting enzyme insertion/deletion polymorphism and proliferative retinopathy in type 2 diabetes. Diabetes Res Clin Pract 81(3):e1–e4CrossRefPubMedGoogle Scholar
  13. 13.
    Viswanathan V, Zhu Y, Bala K, Dunn S, Snehalatha C, Ramachandran A, Jayaraman M, Sharma K (2001) Association between ACE gene polymorphism and diabetic nephropathy in South Indian patients. JOP 2:83–87PubMedGoogle Scholar
  14. 14.
    Ha SK, Park HC, Park HS, Kang BS, Lee TH, Hwang HJ, Kim SJ, Kim DH, Kang SW, Choi KH, Lee HY, Han DS (2003) ACE gene polymorphism and progression of diabetic nephropathy in Korean type 2 diabetic patients: effect of ACE gene DD on the progression of diabetic nephropathy. Am J Kidney Dis 41:943–949CrossRefPubMedGoogle Scholar
  15. 15.
    van Ittersum FJ, de Man AM, Thijssen S, de Knijff P, Slagboom E, Smulders Y, Tarnow L, Donker AJ, Bilo HJ, Stehouwer CD (2000) Genetic polymorphisms of the renin-angiotensin system and complications of insulin-dependent diabetes mellitus. Nephrol Dial Transpl 15(7):1000–1007CrossRefGoogle Scholar
  16. 16.
    Marre M, Bernadet P, Gallois Y, Savagner F, Guyene TT, Hallab M, Cambien F, Passa P, Alhenc-Gelas F (1994) Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes 43:384–388CrossRefPubMedGoogle Scholar
  17. 17.
    Wu SS, Guo QM, Liu GL, Zhang J, Zhao CF, Ning SC, Zhao LN, Yu F, Yi HL (2004) The relationship of angiotensin I-converting enzyme gene polymorphism with diabetic retinopathy and diabetes myocardial infarction. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 21:283–285PubMedGoogle Scholar
  18. 18.
    Nagi DK, Mansfield MW, Stickland MH, Grant PJ (1995) Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and diabetic retinopathy in subjects with IDDM and NIDDM. Diabet Med 12:997–1001CrossRefPubMedGoogle Scholar
  19. 19.
    Yoshida H, Kuriyama S, Atsumi Y, Tomonari H, Mitarai T, Hamaguchi A, Kubo H, Kawaguchi Y, Kon V, Matsuoka K, Ichikawa I, Sakai O (1996) Angiotensin I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus. Kidney Int 50:657–664CrossRefPubMedGoogle Scholar
  20. 20.
    Gutiérrez C, Vendrell J, Pastor R, Llor C, Aguilar C, Broch M, Richart C (1997) Angiotensin I-converting enzyme and angiotensinogen gene polymorphisms in non-insulin-dependent diabetes mellitus. Lack of relationship with diabetic nephropathy and retinopathy in a Caucasian Mediterranean population. Metabolism 46:976–980CrossRefPubMedGoogle Scholar
  21. 21.
    Rabensteiner D, Abrahamian H, Irsigler K, Hermann KM, Kiener HP, Mayer G, Kaider A, Retal Prager (1999) ACE gene polymorphism and proliferative retinopathy in type 1 diabetes: results of a case–control study. Diabetes Care 22(9):1530–1535CrossRefPubMedGoogle Scholar
  22. 22.
    Liao L, Lei M, Chen H, Han X, Fan C (1999) Studies on ACE gene insertion/deletion polymorphism, serum ACE activity and diabetic retinopathy in type II diabetic patients. Hunan Yi Ke Da Xue Xue Bao 24:33–36PubMedGoogle Scholar
  23. 23.
    Matsumoto A, Iwashima Y, Abiko A, Morikawa A, Sekiguchi M, Eto M, Makino I (2000) Detection of the association between a deletion polymorphism in the gene encoding angiotensin I-converting enzyme and advanced diabetic retinopathy. Diabetes Res Clin Pract 50:195–202CrossRefPubMedGoogle Scholar
  24. 24.
    Araz M, Yilmaz N, Güngör K, Okan V, Kepekci Y, Sükrü Aynacioglu A (2001) Angiotensin-converting enzyme gene polymorphism and microvascular complications in Turkish type 2 diabetic patients. Diabetes Res Clin Pract 54(2):95–104CrossRefPubMedGoogle Scholar
  25. 25.
    Degirmenci I, Kebapci N, Basaran A, Efe B, Gunes HV, Akalin A, Kurt H, Urhan M, Demirustu C (2005) Frequency of angiotensin-converting enzyme gene polymorphism in Turkish type 2 diabetic patients. Int J Clin Pract 59:1137–1142CrossRefPubMedGoogle Scholar
  26. 26.
    Wong TY, Chan JC, Poon E, Li PK (1999) Lack of association of angiotensin-converting enzyme (DD/II) and angiotensinogen M235T gene polymorphism with renal function among Chinese patients with type II diabetes. Am J Kidney Dis 33:1064–1070CrossRefPubMedGoogle Scholar
  27. 27.
    Rema M, Saravanan G, Deepa R, Mohan V (2002) Familial clustering of diabetic retinopathy in South Indian Type 2 diabetic patients. Diabet Med 19:910–916CrossRefPubMedGoogle Scholar
  28. 28.
    The Diabetes Control Complications Trial Research Group (1997) Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes 46:1829–1839CrossRefGoogle Scholar
  29. 29.
    Hallman DM, Huber JC Jr, Gonzalez VH, Klein BE, Klein R, Hanis CL (2005) Familial aggregation of severity of diabetic retinopathy in Mexican Americans from Starr County, Texas. Diabetes Care 28:1163–1168CrossRefPubMedGoogle Scholar
  30. 30.
    Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC (1998) Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima diabetes genes group. Diabetes 47:821–830CrossRefPubMedGoogle Scholar
  31. 31.
    Warpeha KM, Chakravarthy U (2003) Molecular genetics of microvascular disease in diabetic retinopathy. Eye 17:305–311CrossRefPubMedGoogle Scholar
  32. 32.
    Hietala K, Forsblom C, Summanen P, Groop PH, Finn Diane Study Group (2008) Heritability of proliferative diabetic retinopathy. Diabetes 57:2176–2180CrossRefPubMedGoogle Scholar
  33. 33.
    Slager SL, Schaid DJ (2001) Case–control studies of genetic markers: power and sample size approximations for Armitage’s test for trend. Hum Hered 52:149–153CrossRefPubMedGoogle Scholar
  34. 34.
    Ye S, Dhillon S, Seear R, Dunleavey L, Day LB, Bannister W, Day IN, Simpson I (2003) Epistatic interaction between variations in the angiotensin I converting enzyme and angiotensin II type 1 receptor genes in relation to extent of coronary atherosclerosis. Heart 89:1195–1199CrossRefPubMedGoogle Scholar
  35. 35.
    Tsai CT, Hwang JJ, Ritchie MD, Moore JH, Chiang FT, Lai LP, Hsu KL, Tseng CD, Lin JL, Tseng YZ (2007) Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene–gene interaction. Atherosclerosis 195:172–180CrossRefPubMedGoogle Scholar
  36. 36.
    Ng DP, Tai BC, Lim XL (2008) Is the presence of retinopathy of practical value in defining cases of diabetic nephropathy in genetic association studies? The experience with the ACE insertion/deletion polymorphism in 53 studies comprising 17, 791 subjects. Diabetes 57:2541–2546CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Endocrinology, Beijing Tongren HospitalCapital Medical UniversityBeijingChina

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