Renin–Angiotensin–Aldosterone System Gene Polymorphisms and Type 2 Diabetic Nephropathy in Asian Populations: An Updated Meta-analysis

Author(s): Norfazilah Ahmad, Rahman Jamal *, Shamsul Azhar Shah, Abdul Halim Abdul Gafor, Nor Azian Abdul Murad.

Journal Name: Current Diabetes Reviews

Volume 15 , Issue 4 , 2019

Become EABM
Become Reviewer


Background: The association of polymorphisms in the renin-angiotensin-aldosterone system candidate genes, namely Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D), Angiotensinogen (AGT) M235T and Angiotensin II Receptor Type 1 (AGTR1) A1166C with Diabetic Nephropathy (DN) has been studied for decades.

Objective: This meta-analysis aimed to assess the updated pooled effects of these polymorphisms with DN among Asian populations with type 2 diabetes mellitus.

Methods: The PubMed electronic database was searched without duration filter until August 2017 and the reference list of eligible studies was screened. The association of each polymorphism with DN was examined using odds ratio and its 95% confidence interval based on dominant, recessive and allele models. Subgroup analyses were conducted based on region, DN definition and DM duration.

Results: In the main analysis, the ACE I/D (all models) and AGTR1 A1166C (dominant model) showed a significant association with DN. The main analysis of the AGT M235T polymorphism did not yield significant findings. There were significant subgroup differences and indication of significantly higher odds for DN in terms of DM duration (≥10 years) for ACE I/D (all models), AGT M235T (recessive and allele models) and AGTR1 A1166C (recessive model). Significant subgroup differences were also observed for DN definition (advanced DN group) and region (South Asia) for AGTR1 A1166C (recessive model).

Conclusion: In the Asian populations, ACE I/D and AGTR1 A1166C may contribute to DN susceptibility in patients with T2DM by different genetic models. However, the role of AGT M235T needs to be further evaluated.

Keywords: Type 2 diabetes mellitus, diabetic nephropathy, ACE I/D, AGT M235T, AGTR1 A1166C, renin-angiotensinaldosterone system, Asian.

National_Geographic_Society. Asia: Human Geography; Culture and Politics. Available from:
Ramachandran A, Snehalatha C, Shetty AS, Nanditha A. Trends in prevalence of diabetes in Asian countries. World J Diabetes 2012; 3(6): 110-7.
International Diabetes Federation IDF Diabetes Atlas 8th edn. Brussels, Belgium:International Diabetes Federation, 2017. Available from.
Shah A, Kanaya AM. Diabetes and associated complications in the south asian population. Curr Cardiol Rep 2014; 16(5): 476.
Brennan E, McEvoy C, Sadlier D, Godson C, Martin F. The genetics of diabetic nephropathy. Genes 2013; 4(4): 596-619.
Toth-Manikowski S, Atta MG. Diabetic kidney disease: pathophysiology and therapeutic targets. J Diabetes Res 2015; 2015: 16.
Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl 2005; (99): S57-65.
Crisan D, Carr J. Angiotensin I-converting enzyme: genotype and disease associations. JMD 2000; 2(3): 105-15.
Gumprecht J, Zychma MJ, Grzeszczak W, Zukowska-Szczechowska E. the End-Stage Renal Disease Study G. Angiotensin I-converting enzyme gene insertion/deletion and angiotensinogen M235T polymorphisms: Risk of chronic renal failure. Kidney Int 2000; 58(2): 513-9.
Braliou GG, Grigoriadou A-MG, Kontou PI, Bagos PG. The role of genetic polymorphisms of the Renin–Angiotensin System in renal diseases: A meta-analysis. Comput Struct Biotechnol J 2014; 10(16): 1-7.
Mooyaart AL, Valk EJ, van Es LA, et al. Genetic associations in diabetic nephropathy: a meta-analysis. Diabetologia 2011; 54(3): 544-53.
Ding W, Wang F, Fang Q, Zhang M, Chen J, Gu Y. Association between two genetic polymorphisms of the renin-angiotensin-aldosterone system and diabetic nephropathy: a meta-analysis. Mol Biol Rep 2012; 39(2): 1293-303.
Wang F, Fang Q, Yu N, et al. Association between genetic polymorphism of the angiotensin-converting enzyme and diabetic nephropathy: a meta-analysis comprising 26,580 subjects. J Renin Angiotensin Aldosterone Syst 2012; 13(1): 161-74.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6(7): e1000097.
Kavvoura FK, Ioannidis JPA. Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls. Hum Genet 2008; 123(1): 1-14.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414): 557-60.
Cochran WG. Some methods for strengthening the common chi-square test. Biometrics 1954; 10(4): 417-51.
Zintzaras E, Lau J. Synthesis of genetic association studies for pertinent gene–disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol 2008; 61(7): 634-45.
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109): 629.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50(4): 1088-101.
Wang Y, Peng W, Zhang X, et al. The association of ACE gene polymorphism with diabetic kidney disease and renoprotective efficacy of valsartan. J Renin Angiotensin Aldosterone Syst 2016; 17(3): 1470320316666799.
Parchwani DN, Palandurkar KM, Hema Chandan Kumar D, Patel DJ. Genetic predisposition to diabetic nephropathy: evidence for a role of ACE (I/D) gene polymorphism in type 2 diabetic population from Kutch region. IJCB 2015; 30(1): 43-54.
Shaikh R, Shahid SM, Mansoor Q, Ismail M, Azhar A. Genetic variants of ACE (Insertion/Deletion) and AGT (M268T) genes in patients with diabetes and nephropathy. J Renin Angiotensin Aldosterone Syst 2014; 15(2): 124-30.
Kumar R, Sharma RK, Agarwal S. Genetic predisposition for development of nephropathy in type 2 diabetes mellitus. Biochem Genet 2013; 51(11-12): 865-75.
Shah VN, Cheema BS, Sharma R, et al. ACAC beta gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes. Mol Cell Biochem 2013; 372(1-2): 191-8.
Rahimi Z, Hasanvand A, Felehgari V. Interaction of MTHFR 1298C with ACE D allele augments the risk of diabetic nephropathy in Western Iran. DNA Cell Biol 2012; 31(4): 553-9.
Al-Harbi EM, Farid EM, Gumaa KA, Masuadi EM, Singh J. Angiotensin-converting enzyme gene polymorphisms and T2DM in a case-control association study of the Bahraini population. Mol Cell Biochem 2011; 350(1-2): 119-25.
Jayapalan JJ, Muniandy S, Chan SP. Null association between ACE gene I/D polymorphism and diabetic nephropathy among multiethnic Malaysian subjects. Indian J Hum Genet 2010; 16(2): 78-86.
Ahluwalia TS, Ahuja M, Rai TS, et al. ACE variants interact with the RAS pathway to confer risk and protection against type 2 diabetic nephropathy. DNA Cell Biol 2009; 28(3): 141-50.
Naresh VVS, Reddy ALK, Sivaramakrishna G, Sharma PVGK, Vardhan RV, Kumar VS. Angiotensin converting enzyme gene polymorphism in type II diabetics with nephropathy. Indian J Nephrol 2009; 19(4): 145-8.
Tien KJ, Hsiao JY, Hsu SC, et al. Gender-dependent effect of ACE I/D and AGT M235T polymorphisms on the progression of urinary albumin excretion in Taiwanese with type 2 diabetes. Am J Nephrol 2009; 29(4): 299-308.
Nikzamir A, Nakhjavani M, Golmohamadi T, Dibai L. Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with metabolic syndrome in Iranians with type 2 diabetes mellitus. Arch Iran Med 2008; 11(1): 3-9.
Movva S, Alluri RV, Komandur S, et al. Relationship of angiotensin-converting enzyme gene polymorphism with nephropathy associated with Type 2 diabetes mellitus in Asian Indians. J Diabetes Complications 2007; 21(4): 237-41.
Osawa N, Koya D, Araki S, et al. Combinational effect of genes for the renin-angiotensin system in conferring susceptibility to diabetic nephropathy. J Hum Genet 2007; 52(2): 143-51.
Prasad P, Tiwari AK, Kumar KM, et al. Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms. BMC Med Genet 2006; 7: 42.
So WY, Ma RC, Ozaki R, et al. Angiotensin-converting enzyme (ACE) inhibition in type 2, diabetic patients-- interaction with ACE insertion/deletion polymorphism. Kidney Int 2006; 69(8): 1438-43.
Park HC, Choi SR, Kim BS, et al. Polymorphism of the ACE Gene in dialysis patients: overexpression of DD genotype in type 2 diabetic end-stage renal failure patients. Yonsei Med J 2005; 46(6): 779-87.
Ha SK, Park HC, Park HS, et al. 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. AKJD 2003; 41(5): 943-9.
Okuno S, Utsugi T, Ohno T, et al. Angiotensin-converting enzyme gene polymorphism as a potent risk factor for developing microalbuminuria in Japanese patients with type 2 diabetes mellitus: a 9-year follow-up study. J Int Med Res 2003; 31(4): 290-8.
Lee YJ, Tsai JC. ACE gene insertion/deletion polymorphism associated with 1998 World Health Organization definition of metabolic syndrome in Chinese type 2 diabetic patients. Diabetes Care 2002; 25(6): 1002-8.
Gohda T, Makita Y, Shike T, et al. Association of the DD genotype and development of Japanese type 2 diabetic nephropathy. Clin Nephrol 2001; 56(6): 475-80.
Taniwaki H, Ishimura E, Matsumoto N, Emoto M, Inaba M, Nishizawa Y. Relations between ACE gene and ecNOS gene polymorphisms and resistive index in type 2 diabetic patients with nephropathy. Diabetes Care 2001; 24(9): 1653-60.
Thomas GN, Critchley JA, Tomlinson B, et al. Albuminuria and the renin-angiotensin system gene polymorphisms in type-2-diabetic and in normoglycemic hypertensive Chinese. Clin Nephrol 2001; 55(1): 7-15.
Viswanathan V, Zhu Y, Bala K, et al. Association between ACE gene polymorphism and diabetic nephropathy in South Indian patients. JOP 2001; 2(2): 83-7.
Hsieh MC, Lin SR, Hsieh TJ, et al. Increased frequency of angiotensin-converting enzyme DD genotype in patients with type 2 diabetes in Taiwan. Nephrol Dial Transplant 2000; 15(7): 1008-13.
Kuramoto N, Iizuka T, Ito H, et al. Effect of ACE gene on diabetic nephropathy in NIDDM patients with insulin resistance. AJKD 1999; 33(2): 276-81.
Tomino Y, Makita Y, Shike T, et al. Relationship between polymorphism in the angiotensinogen, angiotensin-converting enzyme or angiotensin II receptor and renal progression in Japanese NIDDM patients. Nephron 1999; 82(2): 139-44.
Wang J, Zhu X, Yang L, Liu Y, Zhou W, Li H. Relationship between angiotensinogen gene M235T variant with diabetic nephropathy in Chinese NIDDM. Chin Med J 1999; 112(9): 797-800.
Wong TY, Chan JC, Poon E, Li PK. Lack of association of angiotensin-converting enzyme (DD/II) and angiotensinogen M235T gene polymorphism with renal function among Chinese patients with type II diabetes. AJKD 1999; 33(6): 1064-70.
Hanyu O, Hanawa H, Nakagawa O, et al. Polymorphism of the angiotensin I-converting enzyme gene in diabetic nephropathy in type II diabetic patients with proliferative retinopathy. Ren Fail 1998; 20(1): 125-33.
Kimura H, Gejyo F, Suzuki Y, Suzuki S, Miyazaki R, Arakawa M. Polymorphisms of angiotensin converting enzyme and plasminogen activator inhibitor-1 genes in diabetes and macroangiopathy. Kidney Int 1998; 54(5): 1659-69.
Wu S, Xiang K, Weng Q, et al. Relationship between angiotensin I converting enzyme gene polymorphism and diabetic nephropathy. Chin Med J 1998; 111(5): 478-9.
Young RP, Chan JC, Critchley JA, Poon E, Nicholls G, Cockram CS. Angiotensinogen T235 and ACE insertion/deletion polymorphisms associated with albuminuria in Chinese type 2 diabetic patients. Diabetes Care 1998; 21(3): 431-7.
Doi Y, Yoshizumi H, Yoshinari M, et al. Association between a polymorphism in the angiotensin-converting enzyme gene and microvascular complications in Japanese patients with NIDDM. Diabetologia 1996; 39(1): 97-102.
Nakajima S, Baba T, Yajima Y. Is ACE gene polymorphism a useful marker for diabetic albuminuria in Japanese NIDDM patients? Diabetes Care 1996; 19(12): 1420-2.
Ohno T, Kawazu S, Tomono S. Association analyses of the polymorphisms of angiotensin-converting enzyme and angiotensinogen genes with diabetic nephropathy in Japanese non-insulin-dependent diabetics. Metabolism Clin Exp 1996; 45(2): 218-22.
Yoshida H, Kuriyama S, Atsumi Y, et al. Angiotensin I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus. Kidney Int 1996; 50(2): 657-64.
Mizuiri S, Hemmi H, Inoue A, et al. Angiotensin-converting enzyme polymorphism and development of diabetic nephropathy in non-insulin-dependent diabetes mellitus. Nephron 1995; 70(4): 455-9.
Ma RCW, Chan JCN. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci 2013; 1281(1): 64-91.
Shrivastava U, Misra A, Mohan V, Unnikrishnan R, Bachani D. Obesity, diabetes and cardiovascular diseases in India: public health challenges. Curr Diabetes Rev 2017; 13: 65-80.
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86(4): 1343-6.
Felehgari V, Rahimi Z, Mozafari H, Vaisi-Raygani A. ACE gene polymorphism and serum ACE activity in Iranians type II diabetic patients with macroalbuminuria. Mol Cell Biochem 2011; 346(1-2): 23-30.
El-Baz R, Settin A, Ismaeel A, et al. MTHFR C677T, A1298C and ACE I/D polymorphisms as risk factors for diabetic nephropathy among type 2 diabetic patients. J Renin Angiotensin Aldosterone Syst 2012; 13(4): 472-7.
Šeruga M, Makuc J, Završnik M, Cilenšek I, Ekart R, Petrovič D. Polymorphism of angiotensin-converting enzyme (rs4340) and diabetic nephropathy in Caucasians with type 2 diabetes mellitus. Balkan J Med Genet 2016; 19(2): 29-34.
Arfa I, Abid A, Nouira S, et al. Lack of association between the angiotensin-converting enzyme gene (I/D) polymorphism and diabetic nephropathy in Tunisian type 2 diabetic patients. J Renin Angiotensin Aldosterone Syst 2008; 9(1): 32-6.
Haque SF, Ahmad M, Khan AU, Gupta V, Khan AS. Angiotensin converting enzyme insertion/deletion gene polymorphism and genomic sequence in diabetic nephropathy. Biomed Res 2011; 22(2): 175-9.
Patel HV, Kalia K, Mannari J. Angiotensin converting enzyme (ACE) gene polymorphism increases the susceptibility of diabetic nephropathy in Western Indian Type 2 diabetic patients. Int J Diabetes Dev Ctries 2011; 31(4): 223-8.
Bhaskar LV, Mahin S, Ginila RT, Soundararajan P. Role of the ACE ID and PPARG P12A polymorphisms in genetic susceptibility of diabetic nephropathy in a south Indian population. Nephrourol Mon 2013; 5(3): 813-7.
Zafarmand MH, van der Schouw YT, Grobbee DE, de Leeuw PW, Bots ML. The M235T polymorphism in the AGT gene and CHD risk: evidence of a hardy-weinberg equilibrium violation and publication bias in a meta-analysis. PLoS One 2008; 3(6): e2533.
Watkins WS, Rohrwasser A, Peiffer A, Leppert MF, Lalouel J-M, Jorde LB. AGT genetic variation, plasma AGT, and blood pressure: an analysis of the Utah Genetic Reference Project pedigrees. Am J Hypertens 2010; 23(8): 917-23.
Say Y-H, Ling K-H, Duraisamy G, Isaac S, Rosli R. Angiotensinogen M235T gene variants and its association with essential hypertension and plasma renin activity in Malaysian subjects: A case control study. BMC Cardiovasc Disord 2005; 5(1): 7.
Mottl AK, Shoham DA, North KE. Angiotensin II type 1 receptor polymorphisms and susceptibility to hypertension: A HuGE review. Genet Med 2008; 10(8): 560-74.
Moradi M, Rahimi Z, Amiri S, Rahimi Z, Vessal M, Nasri H. AT1R A1166C variants in patients with type 2 diabetes mellitus and diabetic nephropathy. J Nephropathol 2015; 4(3): 69-76.
Makuc J, Šeruga M, Završnik M, Cilenšek I, Petrovič D. Angiotensinogen (AGT) gene missense polymorphisms (rs699 and rs4762) and diabetic nephropathy in Caucasians with type 2 diabetes mellitus. Bosn J Basic Med Sci 2017; 17(3): 262-7.
Reis KA, Ebinc FA, Koc E, et al. Association of the angiotensinogen M235T and APO E gene polymorphisms in Turkish type 2 diabetic patients with and without nephropathy. Ren Fail 2011; 33(5): 469-74.
MacIsaac RJ, Ekinci EI, Jerums G. Markers of and risk factors for the development and progression of diabetic kidney disease . AJKD 63(2): S39-S62.
Yu ZY, Chen LS, Zhang LC, Zhou TB. Meta-analysis of the relationship between ACE I/D gene polymorphism and end-stage renal disease in patients with diabetic nephropathy. Nephrology 2012; 17(5): 480-7.
Ottman R. Gene–environment interaction: definitions and study designs. Prev Med 1996; 25(6): 764-70.
Salanti G, Southam L, Altshuler D, et al. Underlying genetic models of inheritance in established type 2 diabetes associations. Am J Epidemiol 2009; 170(5): 537-45.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [263 - 276]
Pages: 14
DOI: 10.2174/1573399814666180709100411
Price: $58

Article Metrics

PDF: 16
PRC: 1