The insertion/deletion polymorphism of the angiotensin-converting enzyme gene is associated with progression,but not development,of albuminuria in Iranian patients with type 2 diabetes
Restricted accessOtherFirst published online June, 2009
The insertion/deletion polymorphism of the angiotensin-converting enzyme gene is associated with progression,but not development,of albuminuria in Iranian patients with type 2 diabetes
Introduction. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been shown to be associated with a number of complications of type 2 diabetes. Results on the development and progression of albuminuria, however, have remained controversial, with ethnic differences being a potential reason.The present study is the first report to examine Iranian patients. Methods. Patients (322; 162 males) with type 2 diabetes were categorised in this cross-sectional study into the following groups: normoalbuminuria (n=145), microalbuminuria (n=129) and macroalbuminuria (n=48).ACE gen I/D polymorphism genotypes were determined using the polymerase chain reaction method. Results. The distribution of ACE genotypes was significantly different among the groups (p<0.001), with the II genotype decreasing and the DD genotype increasing in frequency with increasing severity of albuminuria. Multivariate regression analysis showed that the ACE genotype did not change the odds of having microalbuminuria versus normoalbuminuria, while the D allele independently increased the odds of having macroalbuminuria versus microalbuminuria approximately threefold (p<0.01).
Conclusions. In Iranian patients with type 2 diabetes, the D allele is associated with progression, but not development, of albuminuria.
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 Clin Invest1990;86:1343-6.
2.
Tiret L., Rigat B., Visvikis S. et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet1992;51:197-205.
3.
Jacobsen PKPreventing end stage renal disease in diabetic patients - genetic aspect (part I). J Renin Angiotensin Aldosterone Syst2005 ;6:1-14.
4.
Investigators for HOPE study.Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet2000;355:253-9.
5.
Brenner BM, Cooper ME, de Zeeuw D. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med2001;345:861-9.
6.
Ruggenenti P. , Bettinaglio P., Pinares F., Remuzzi G.Angiotensin converting enzyme insertion/deletion polymorphism and renoprotection in diabetic and nondiabetic nephropathies . Clin J Am Soc Nephrol2008;3:1511-25.
7.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care2003;26:S5-20.
8.
Aiello LP, Gardner TW, King GL et al. Diabetic retinopathy. Diabetes Care1998;21:143-56.
9.
Nakhjavani M. , Esfahanian F., Jahanshahi A. et al. The relationship between the insertion/deletion polymorphism of the ACE gene and hypertension in Iranian patients with type 2 diabetes. Nephrol Dial Transplant2007;22:2549-53.
10.
Lieberman J.Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. Am J Med1975;59:365-72.
11.
Lieberman J.The specificity and nature of serum-angiotensin-converting enzyme (serum ACE) elevations in sarcoidosis. Ann N Y Acad Sci1976;278:488-97.
12.
Feghhi M., Nikzamir A., Esteghamati A., Farahi F., Nakhjavani M., Rashidi A.The relationship between angiotensin-converting enzyme insertion/deletion polymorphism and proliferative retinopathy in type 2 diabetes. Diabetes Res Clin Pract2008;81:1-4.
13.
Marre M., Bernadet P., Gallois Y. et al. Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes1994;43:384-8.
14.
Doria A., Warram JH, Krolewski ASGenetic predisposition to diabetic nephropathy: evidence for a role of the angiotensin I converting enzyme gene. Diabetes1994;43:690-5.
15.
Marre M., Jeunemaitre X., Gallois Y. et al. Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group. J Clin Invest1997;99:1585-95.
16.
Hadjadj S., Belloum R., Bouhanick B. et al. Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study. J Am Soc Nephrol2001;12:541-9.
17.
Schmidt S., Schöne N., Ritz E.Association of ACE gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group. Kidney Int1995;47:1176-81.
18.
Pfohl M., Frost D., Koch M. et al. Lack of association between the insertion/deletion polymorphism of the angiotensin-converting-enzyme gene and diabetic nephropathy in IDDM patients. Horm Metab Res1998;30:276-80.
19.
Schmidt S., Strojek K., Grzeszczak W., Bergis K., Ritz E.Excess of DD homozygotes in haemodialysed patients with type II diabetes. The Diabetic Nephropathy Study Group. Nephrol Dial Transplant1997;12:427-9.
20.
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 Syst2008;9:32-6.
21.
Hadjadj S., Gallois Y., Alhenc-Gelas F. et al. Angiotensin-I-converting enzyme insertion/deletion polymorphism and high urinary albumin concentration in French type 2 diabetes patients . Diabet Med2003;20:677-82.
22.
Mizuiri S., Hemmi H., Inoue A. et al. Angiotensin-converting-enzyme polymorphism and development of diabetic nephropathy in non-insulin-dependent diabetes mellitus. Nephron1995;70:455-9.
23.
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 Res2003;31:290-8.
24.
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 Transplant2000;15:1008-13.
25.
Jacobsen PK, Tarnow L., Parving HHTime to consider ACE insertion/deletion genotypes and individual renoprotective treatment in diabetic nephropathy?Kidney Int2006;69:1293-5.
26.
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. Am J Kidney Dis2003 ;41:943-9.
27.
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 Int2006;69:1438-43.
28.
Moriyama T. , Kitamura H., Ochi S. 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 Nephrol1995;6:1676-8.
29.
Ha SK, Yong Lee S., Su Park H. 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 Transplant2000;15:1617-23.
30.
Scharplatz M., Puhan MA, Steurer J. et al. Does the angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? A systematic review. Curr Control Trials Cardiovasc Med2005;6:16-27.
31.
Nikzamir A. , Nakhjavani M., Esteghamati A., Rashidi A.Correlates of ACE activity in macroalbuminuric type 2 diabetic patients treated with chronic ACE inhibition. Nephrol Dial Transplant2008 ;23:1274-7.
