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ORIGINAL ARTICLE
Year : 2009  |  Volume : 19  |  Issue : 4  |  Page : 145-148
 

Angiotensin converting enzyme gene polymorphism in type II diabetics with nephropathy


1 Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Sri Venkateswara University, Tirupati - 517 507, India
2 Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Sri Venkateswara University, Tirupati - 517 507, India
3 Department of Statistics, Sri Venkateswara Institute of Medical Sciences, Sri Venkateswara University, Tirupati - 517 507, India

Date of Web Publication22-Jan-2010

Correspondence Address:
V Siva Kumar
Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Tirupati - 517 507, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-4065.59335

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  Abstract 

Nephropathy is an important and a frequent complication of long-term type II diabetic nephropathy. Strong evidence exists that genetic predisposition plays a major role in the development of diabetic nephropathy. Recent studies have implicated association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and nephropathy. The deletion gene polymorphism of ACE gene has been shown to be associated with increased activity of this enzyme. This study examines the association of ACE I/D polymorphism with type II diabetes without nephropathy in 30 patients and type II diabetes with nephropathy in 30 patients. The results of the study suggest the association between the DD polymorphism and type II diabetes with nephropathy.


Keywords: Angiotensin converting enzyme gene polymorphism, nephropathy, type II diabetes mellitus


How to cite this article:
Naresh V, Reddy A, Sivaramakrishna G, Sharma P, Vardhan R V, Kumar V S. Angiotensin converting enzyme gene polymorphism in type II diabetics with nephropathy. Indian J Nephrol 2009;19:145-8

How to cite this URL:
Naresh V, Reddy A, Sivaramakrishna G, Sharma P, Vardhan R V, Kumar V S. Angiotensin converting enzyme gene polymorphism in type II diabetics with nephropathy. Indian J Nephrol [serial online] 2009 [cited 2019 Sep 22];19:145-8. Available from: http://www.indianjnephrol.org/text.asp?2009/19/4/145/59335



  Introduction Top


Chronic kidney disease (CKD) is a global threat to the health in general and for developing countries, in particular, because therapy is expensive and life-long. The estimated prevalence rate in CKD was 0.78% in India. If this data is applied to one billion population of India, there are approximately 7.85 million CRF patients in our country. Diabetes constitutes about 41% of the spectrum of the CKD. [1]

It is predicted that worldwide the prevalence of diabetes in adults would increase to 5.4% by the year 2024, from the prevalence rate of 4% in 1995. Consequently, the number of adults with diabetes in the world would rise from 135 million in 1995 to 300 million in the year 2025. While a 42% increase is expected in developed countries, a 170% increase is expected in the developing countries. Therefore, diabetic patients in the developing countries are even more vulnerable to develop the microvascular complications of diabetes including diabetic nephropathy. [2]

Strong evidence exists that genetic predisposition plays a significant role in the development of diabetic nephropathy in both type I and type II diabetes mellitus (DM).

Studies have shown that renin-angiotensin system may play an important role in the development of nephropathy in type II DM, and thus, the angiotensin converting enzyme (ACE) polymorphism may be a potential predictor for development of nephropathy in type II DM. [3],[4]

ACE catalyses production of the vaso active peptide Angiotensin II from its precursor Angiotensin I. Within the diabetic kidney the effects of Angiotensin II include an increase of intraglomerular pressure and glomerular filtration rate. In addition to its hemodynamic effects Angiotensin II stimulates the production or release of several cytokine mediators of glomerulosclerosis such as Osteopontin, Platelet derived growth factor, Fibronectin and Transforming growth factor b. [3]

Genetic studies have revealed that the genes of renin angiotensin system (RAS) are highly polymorphic, raising the possibility that in addition to environmental factors, the genetic make up of RAS affects the status of RAS in individuals. One of such is the insertion/deletion (I/D) polymorphism of ACE gene. The ACE gene consists of 26 exons and spans 21 kb, on chromosome 17. Within intron 16, the polymorphism exists, consisting of the presence or absence of a 287 base-pair fragment. [5]

The deletion polymorphism is associated with elevated serum and cellular ACE levels. Earlier studies measuring plasma and tissue ACE levels demonstrated a significantly positive correlation between the D-allele and the RAS in normal subjects. It is observed that the II genotype has lowest ACE levels, the DD type has the highest and ID has the intermediate levels. [4],[5],[6],[7]

The primary objective of the study was to find out pattern of distribution of ACE gene polymorphism in healthy controls, in patients of type II DM without nephropathy, in patients of type II DM with nephropathy and to study the relation between DD polymorphism and diabetes with nephropathy.


  Materials and Methods Top


This was a prospective study of two years duration (2006-2008) undertaken in our institute, after obtaining ethical clearance and patients consent to study the ACE gene polymorphism in type II DM patients with and without nephropathy. This study was carried out in three groups: normal controls (n = 30), type II diabetcis without nephropathy (n 5 30), type II diabetics with nephropathy (n = 30) in our hospital during 2006-2008. This study was conducted after obtaining ethical clearance and patient consent. Adult patients with overnight fasting plasma glucose of more than 126 mg/dl on two consecutive days were included in type II diabetes mellitus (DM) category. Type II DM patients with 24 hours urinary protein of more than 500 mg with evidence of diabetic retinopathy were included in diabetic nephropathy group.

Determination of ACE genotype: DNA was isolated from 2 ml of whole-blood sample. [8] PCR amplification to detect ACE I/D polymorphism was carried out using the following primers: 5'-CTGGAGACCACTCCCATCCTTTCT-3' and 5'-GATGTGGCCATCACATTCGTCAGAT-3'. Amplification with this primer pair produces products of ~490 and 190 bp corresponding to I and D alleles, respectively. Thermo cycling consisted of denaturation at 94C for 60 S, annealing at 65C for 60 S, and extension at 72C for 90 S for 40 cycles followed by final extension at 72C for seven minutes. PCR products (20 μl) were mixed with 4 μl 6X glycerol based gel loading buffer, size fractionated by electrophoresis 1% agarose gel that contained 0.5 mg/ml of ethidium bromide, and visualized by UV Tran illuminator. All D/D samples were amplified with an insertion-specific primer pair, which recognizes the inserted sequences, 5'-TGGGACCACAGCGCCCGCCACTAC-3' and 5'-TCGCCAGCCCTCCCATGCC CATAA-3'. [9],[10] Cycling consisted of 40 cycles of denaturation at 94C for 1 minute, and annealing/extension at 78C for 1 minute, followed by a final extension at 72C for 10 minutes.

Statistical analysis was done using SPSS software version 11.0. Genotype frequencies of ACE gene polymorphism were compared between type II diabetic patients with or without nephropathy using Chi square test. Genotypic and Allelic associations found significant by Chi square test were evaluated by computing odds ratio (OR) and 95% confidence intervals (CI). P values < 0.05 were considered significant.


  Results Top


The demographic and other details of the subjects were summarized in [Table 1]. The ACE gene polymorphism analysis was summarized in [Table 2]. The D allele distribution was significantly increasesd in diabetes with nephropathy patients in comparison to controls. In the similar way DD genotype distribution was strongly increasesd in diabetes with nephropathy patients in comparison to controls. Odds ratio and 95% confidence intervals were shown amongst the groups in [Table 3].


  Discussion Top


The primary objective of the study was to find the pattern of distribution of ACE gene polymorphism in healthy controls, in type II DM without nephropathy, type II DM with nephropathy and to study the relation between DD gene polymorphism and diabetic nephropathy.

Although the data from Caucasian studies failed to confirm an increased risk for the development of diabetic nephropathy in IDDM and NIDDM being associated with D-allele, a role for this genetic marker in Asian patients with NIDDM cannot be ruled out. [11]

Grzeszczak et al. from Poland and Schmidt et al. from Germany did not find any association between the ACE gene polymorphism and nephropathy in NIDDM. [3,6] Yoshida et al. from Japan, Jeffers et al. from USA and Nikzamir et al. from Iran found a strong association betweezn ACE-DD genotype and/or D-allele and the risk for nephropathy in type II DM. [4],[5],[11],[12]

In Indian studies, Viswanathan et al. [13] and Bhavani et al. [14] found a positive association between the D allele (ID and DD genotype) of the ACE polymorphism and diabetic nephropathy in south Indian type II diabetic patients. [13],[14] Where as Ajay Kumar et al. [15] and Prasad P. et al. [16] found no relation between ACE gene polymorphism and development of diabetic nephropathy in type II diabetics in north Indian population.

Parving et al., reduction of end points in NIDDM with the Angiotensin II Antagonist Losartan (RENNAL) study found improvement in renal prognosis with Losartan in the D allele patients of NIDDM. [17]

In our study, a statistically significant relationship was observed between the D allele, DD genotype of the ACE polymorphism and diabetic nephropathy in South Indian type II diabetic nephropathy patients.

 
  References Top

1.Dash SC, Agarwal SK. Incidence of chronic kidney disease in India. Nephrol Dial Transplant 2006;21:232-3.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Viswanathan V. Type 2 diabetes and diabetic nephropathy in India- magnitude of the problem. Nephrol Dial Transplant 1999;14:2805-7.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Grzeszczak W, Zychma MJ, Lacka B, Zukowska-Szczechowska E. Angiotensin I converting enzyme gene polymorphisms: Relationship nephropathy in patients with non insulin dependent diabetes mellitus. J Am Soc Nephrol 1998;9:1664-9.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Jeffers BW, Estacio RO, Raynolds MV, Schrier RW. Angiotensin converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus and its relationship with diabetic nephropathy. Kidney Int 1997;52:473-7.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Yoshida H, Kuriyama S, Atsumi Y, Tomonari H, Mitarai T, Hamaguchi A, et al. Angiotensin I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus. Kidney Int 1996;50:657-64.  Back to cited text no. 5      
6.Schmidt S, Schöne N, Ritz E. Association of ACE gene polymorphism and diabetic ephropathy? Kidney Int 1995;47:1176-81.  Back to cited text no. 6      
7.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;86:1343-6.   Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Sambrook J, Russell D. Molecular Cloning: A laboratory manual. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press; 2001. p. 6.28-.30.  Back to cited text no. 8      
9.Shanmugam V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl 1993;3:120-1.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, et al. A prospective evaluation of an Angiotensin-converting enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706-11.  Back to cited text no. 10      
11.Kunz R, Bork JP, Fritsche L, Ringel J, Sharma AM. Association between the angiotensin converting enzyme insertion/deletion polymorphism and diabetic nephropathy. A methodological appraisal and systematic review. J Am Soc Nephrol 1998;9:1653-63.  Back to cited text no. 11      
12.Nikzamir A, Esteghamati A, Feghhi M, Nakhjavani M, Rashidi A, Reza JZ. Angiotensin converting enzyme gene polymorphism in Iranian patients with type II diabetes. Iran. J Immunol 2006;3:23-9.  Back to cited text no. 12      
13.Viswanathan V, Zhu Y, Bala K, Dunn S, Snehalatha C, Ramachandran A, et al. Association between ACE gene polymorphism and diabetic nephropathy in south Indian patients. J Pancreas 2001;2:83-7.  Back to cited text no. 13      
14.Bhavani BA, Padma T, Sastry BK, Krishna Reddy N, Nausheen K. The insertion i/deletion D polymorphism of Angiotensin converting enzyme (ACE) gene increase the susceptibility to hypertension and/or diabetes. Int J Hum Genet 2005;5:247-52.  Back to cited text no. 14      
15.Kumar A, Mohindru K, Sehajpal PK. Angiotensin I converting enzyme polymorphism and diabetic nephropathy in north India. Int J Hum Genet 2005;5:279-83.  Back to cited text no. 15      
16.Prasad P, Tiwari AK, Kumar KM, Ammini AC, Gupta A, Gupta R, et al. Chronic renal insufficiency among Asian Indians with type II diabetes: I. Role of RAAS gene polymorphisms. BMC Medical Genetics 2006;7:1-9.  Back to cited text no. 16      
17.Parving HH, de Zeeuw D, Cooper ME, Remuzzi G, Liu N, Lunceford J, et al. ACE gene polymorphism and Losartan treatment in type II diabetic patients with nephropathy. J Am Soc Nephrol 2008;19:771-9.  Back to cited text no. 17      



 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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