The role of angiotensin converting enzyme (insertion)/(deletion) and angiotensin II type 1 receptor (A1166C) gene polymorphisms in antiproteinuric effect of ACE inhibitors in type 2 diabetic Iraqi patients

Ansam Abdulameer Yahya Dheyaa Jabbar Kadhim Nassar Abdalaema Abdalhadi   

Open Access   

Published:  May 16, 2024

DOI: 10.7324/JAPS.2024.169478

The angiotensin converting enzyme (ACE) I\D gene polymorphism influences the blood ACE enzyme activity. Renoprotective effect of ACE inhibitors (ACEIs) varies among patients due to genetic variation, particularly in Renin-Angiotensin-Aldosterone System genes. This study investigates the genetic variations of ACE I\D and AGT1RA1166C gene polymorphisms in the antiproteinuric effect of ACEI therapy in type 2 diabetes mellitus (T2DM) patients. This is a cross-sectional study that included 76 T2DM patients who are ACEI users, divided into two groups: T2DM without diabetic kidney disease (DKD) included 31 patients, and T2DM with DKD included 45 patients. Urine samples were taken for measurement of urine albumin and creatinine, then calculation of albumin-creatinine ratio (ACR). Blood samples were taken for the measurement of serum parameters and also for the extraction of DNA for genetic evaluation of ACEI/D and AGT1RA1166C gene polymorphisms. The results reveal that T2DM patients carrying the ID genotype have significantly lower ACE1 levels compared to DD and II carriers (p = 0.012). When grouping patients according to the ACR, serum ACE1 and angiotensin-converting enzyme 2 (ACE2) levels were higher in DKD compared to normalbuminuric patients, with the only significant difference for ACE2. After subdividing according to ACE I\D genotypes, the ACE2 differences were only significant in DD genotype carriers (p = 0.049) between DKD and normalbuminuric groups. While for AGT1RA1166C polymorphisms, the AC genotype shows non-significantly lower levels for ACE1 and ACE2. After subdividing according to AGT1RA1166C genotypes, ACE2 levels were significantly higher in DKD patients carrying the AA genotype (p = 0.015). Binary logistic regression analysis revealed that both ACE (I\D) and AGT1RA1166C genes are significant predictors of ACE1 levels after controlling age, gender, and DKD state. This study concluded that both genes are predictors of ACE1 levels; in addition, ID genotype carriers and AC genotype carriers had lower ACE1 and ACE2 levels with lower ACR and higher glomerular filtration rate, identifying better ACEIs responses in ID and AC carriers.

Keyword:     Angiotensin converting enzyme1 angiotensin converting enzyme2 diabetic kidney disease albumin: creatinine ratio ACE I\D genotype AGT1RA1166C genotype angiotensin converting enzyme inhibitors


Yahya AA, Kadhim DJ, Abdalhadi NA. The role of angiotensin converting enzyme (insertion)/(deletion) and angiotensin II type 1 receptor (A1166C) gene polymorphisms in antiproteinuric effect of ACE inhibitors in type 2 diabetic Iraqi patients. J Appl Pharm Sci. 2024. Online First.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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1. Jasim HS, Altaie AF, Saloum WT, Ali AH. Comparative study of new biomarkers in Iraqi DM2 with and without complications. Rep Biochem Mol Biol. 2022;11(3):400–4. doi:

2. Akram W. Initial recognition and prophecy of diabetic nephropathy in type I diabetes in a sample of Iraqi patients. AL-Kindy Col Med J. 2012;8:94–102.

3. Hamid GS, Allawi AA, Ghudhaib KK. Correlation of pentosidine with kidney diseases in Iraqi patients with diabetic nephropathy. Iraqi J Sci. 2021;62(10):3436–42. Available from:

4. Ali AA, Al Lami FH. Prevalence and determinants of microalbuminurea among type 2 diabetes mellitus patients, Baghdad, Iraq, 2013. Saudi J Kidney Dis Transpl. 2016;27(2):348–55. doi:

5. Salih BH, Ali SH, Allehibi KI. Serum aldosterone levels in patients with diabetic nephropathy in relation to vascular calcification. Iraqi J Pharm Sci. 2019;28:53–63.

6. So WY, Ma RC, Ozaki R, Tong PC, Ng MC, Ho CS, 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. doi:

7. Al-Awadi SJ, Ghareeb MA, Oleiwi AA, Salo WH, Moner AI. Genotype distribution of angiotensin i- converting enzyme in iraqi arab population. Iraqi J Cancer Med Genet. 2011;4(2):24–9.

8. Al-Radeef MY, Fawzi HA, Allawi AA. ACE gene polymorphism and its association with serum erythropoietin and hemoglobin in Iraqi hemodialysis patients. Appl Clin Genet. 2019;12:107–12. doi:

9. Reis AAdS, Silva EGd, Santos KdF, Anjos LRBd, Santos RdS, Freiria-Oliveira AH. Do ACE and ACE2 polymorphisms influence in the pathogenesis of diabetic nephropathy?. Res Sq. 2021. doi:

10. Ha SK. ACE insertion/deletion polymorphism and diabetic nephropathy: clinical implications of genetic information. J Diabetes Res. 2014;2014:846068. doi:

11. Huang K, Liang Y, Wang K, Ma Y, Wu J, Luo H, et al. Elevated ACE levels indicate diabetic nephropathy progression or companied retina impaired. Front Clin Diabetes Healthc. 2022;3:1. doi:

12. Soler MJ, Wysocki J, Batlle D. ACE2 alterations in kidney disease. Nephrol Dial Transplant. 2013;28(11):2687–97. doi:

13. Varagic J, Ahmad S, Nagata S, Ferrario CM. ACE2: angiotensin II/angiotensin-(1-7) balance in cardiac and renal injury. Curr Hypertens Rep. 2014;16(3):420. doi:

14. Zhuang Y, Niu F, Liu D, Sun J, Zhang X, Zhang J, et al. Association between AGTR1 A1166C polymorphism and the susceptibility to diabetic nephropathy: evidence from a meta-analysis. Medicine (Baltimore). 2018;97(41):e07689. doi:

15. Ribeiro-Oliveira A Jr, Nogueira AI, Pereira RM, Boas WW, Dos Santos RA, Simões e Silva AC. The renin-angiotensin system and diabetes: an update. Vasc Health Risk Manag. 2008;4(4):787–803.

16. Toblli JE, Bevione P, Di Gennaro F, Madalena L, Cao G, Angerosa M. Understanding the mechanisms of proteinuria: therapeutic implications. Int J Nephrol. 2012;2012:546039. doi:

17. Moriyama T, Kitamura H, Ochi S, Izumi M, Yokoyama K, Yamauchi A, et al. Association of angiotensin I-converting enzyme gene polymorphism with susceptibility to antiproteinuric effect of angiotensin I-converting enzyme inhibitors in patients with proteinuria. J Am Soc Nephrol. 1995;6(6):1676–8. doi:

18. Ha SK, Yong Lee S, Su Park H, Ho Shin J, Jung Kim S, Hun Kim D, et al. ACE DD genotype is more susceptible than ACE II and ID genotypes to the antiproteinuric effect of ACE inhibitors in patients with proteinuric non-insulin-dependent diabetes mellitus. Nephrol Dial Transplant. 2000;15(10):1617–23. doi:

19. Cheema BS, Kohli HS, Sharma R, Bhansali A, Khullar M. Endothelial nitric oxide synthase gene polymorphisms and renal responsiveness to RAS inhibition therapy in type 2 diabetic Asian Indians. Diabetes Res Clin Pract. 2013;99(3):335–42. doi:

20. Volkan-Salanci B, Dagdelen S, Alikasifoglu M, Erbas T, Hayran M, Erbas B. Impact of renin-angiotensin system polymorphisms on renal haemodynamic responsiveness to acute angiotensin-converting enzyme inhibition in type 2 diabetes mellitus. J Renin Angiotensin Aldosterone Syst. 2009;10(1):41–50. doi:

21. 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. doi:

22. Al-Tukmagi HF, AL-Auqbi TF. Assessment of morisky medication adherence scale (8-mmas) in a sample of iraqi type 2 diabetic patients. IRAQI J Community Med. 2015;28(4):212–5.

23. Biolab. Creatinine kinetic method. Available from:

24. Abnova. BCG albumin assay kit. Available from:

25. Yahya A, Kadhim D, Abdalhadi N. Kidney injury molecule-1 and cystatin C as early biomarkers for renal dysfunction in Iraqi type 2 diabetes mellitus patients. J Adv Biotechnol Exp Ther. 2023;6(3):673–85.

26. Human Cystatin C, CYS-C ELISA Kit, Jiaxing, China.

27. Human Kidney Injury Molecule 1, KIM-1 ELISA Kit, Jiaxing, China.

28. Human Angiotensin Converting Enzyme, ACE ELISA Kit, Jiaxing, China.

29. Human Angiotensin Converting Enzyme 2, ACE2 ELISA Kit, Jiaxing, China.

30. Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New creatinine-and cystatin c–based equations to estimate gfr without race. N Engl J Med. 2021;385:1737–49.

31. Alp E, Menev?e S. Comparison of conventional and real time pcr methods to determine of the ace I/D and angiotensinogen m235t polymorphisms. Marmara Med J. 2009;22:27–33.

32. Halder K, Purkait P. Association of angiotensin II type I receptor (agtr1) gene polymorphism and type2 diabetes & nephropathy among the Eastern Indian Bengali patients. Diabetes Obes Int J Diabetes Obes Int J. 2020;5:1–13.

33. Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL, et al. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinform. 2012;13:134. doi:

34. Yamamoto Y, Hanai K, Mori T, Yokoyama Y, Yoshida N, Murata H, et al. Kidney outcomes and all-cause mortality in people with type 2 diabetes exhibiting non-albuminuric kidney insufficiency. Diabetologia. 2022;65(1):234–45. doi:

35. Ibrahim RK, Ghudhaib KK, Allawi AA. Determining ACE-2 level and some relevant biochemical parameters and studying the effect of gender in Iraqi diabetic patients with glomeruli and renal tubules fibrosis as early prediction marker. Baghdad Sci J. 2023;20(6):2256–64.

36. Aggarwal N, Kare PK, Varshney P, Kalra OP, Madhu SV, Banerjee BD, et al. Role of angiotensin converting enzyme and angiotensinogen gene polymorphisms in angiotensin converting enzyme inhibitor-mediated antiproteinuric action in type 2 diabetic nephropathy patients. World J Diabetes. 2017;8(3):112–9. doi:

37. de Denus S, Dubé MP, Fouodjio R, Huynh T, LeBlanc MH, Lepage S, et al. A prospective study of the impact of AGTR1 A1166C on the effects of candesartan in patients with heart failure. Pharmacogenomics. 2018;19(7):599–612. doi:

38. Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS, et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3’ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet. 2007;81(2):405–13. doi:

39. Miller JA, Thai K, Scholey JW. Angiotensin II type 1 receptor gene polymorphism predicts response to losartan and angiotensin II. Kidney Int. 1999;56(6):2173–80. doi:

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