Abstract
Polymorphism in Renin-Angiotensin-Aldosterone System (RAAS) genes have been studied extensively in various ethnic groups and largely with inconsistent findings on relationship with the risk of developing type 2 diabetes mellitus (T2DM). In this study, we investigated the association of Insertion/Deletion (I/D) polymorphism of angiotensin converting enzyme (ACE) and -344 C/T polymorphism of aldosterone synthase [cytochrome P450 (CYP11B2)] with T2DM in an Emirati population and interactive effects between these two gene polymorphisms on T2DM risk. A total of 243 Emirati subjects (133 healthy control and 110 T2DM patients) were selected for the study. The ACE genotypes were determined by polymerase chain reaction (PCR) followed by agarose gel electrophoresis. The CYP11B2 genotyping was performed by PCR- Restriction Fragment Length Polymorphism Analysis(RFLP). ACE genotypes were not associated with T2DM risk. The frequencies of D allele were 0.68 and 0.64 in the patients and healthy group respectively and the differences were not statistically significant. For CYP11B2 -344C/T polymorphism, CC genotype was found significantly higher in healthy subjects than in T2DM patients (22.1 Vs 9.8%, p=0.016). The subjects with CC genotype were at decreased T2DM risk in the recessive model [Odd ratio 0.38 (0.17-0.84)]. An interactive effect on T2DM risk was found between ACE-ID and CYP11B2 -CC genotypes. In the subjects with combination of ID + CC genotypes, risk of T2DM was further reduced (odd ratio 0.05 vs 1.12). The association of CC with T2DM was independent of age and gender. To date, this study is the first report on association of CYP11B2 -344C/T with T2DM and its possible interaction with ACE I/D polymorphism in an Emirati population. The results suggest that ACE I/D polymorphism does not affect T2DM risk independently however, subjects with CC genotypes either alone or in combination with ACE I/D heterozygote would be at decreased risk of developing T2DM. Key words: Type 2 diabetes mellitus, CYP11B2, Renin-Angiotensin-Aldosterone System, angiotensin converting enzyme, genetic polymorphism
Highlights
Type 2 diabetes mellitus (T2DM) is a disorder characterized by hyperglycemia as a result of impaired insulin secretion and insulin resistance in peripheral tissues
The most likely mechanism by which Renin- Angiotensin-Aldosterone System (RAAS) may affects the risk of T2DM is by alteration in the level of aldosterone which has been found associated with insulin resistance and the ensuing hyperinsulinemia (Colussi et al, 2007) which are major predisposing factors to the development of T2DM
angiotensin converting enzyme (ACE) produces angiotensin II the level of which depends on the availability of angiotensinogen and the potential of its action depends on the availability of the angiotensin II type 1 receptor (AT1R)
Summary
Type 2 diabetes mellitus (T2DM) is a disorder characterized by hyperglycemia as a result of impaired insulin secretion and insulin resistance in peripheral tissues. Polymorphism in RAAS genes in relation to T2DM has been studied intensively and mostly focused on Angiotensin converting enzyme ACE along with angiotensin receptor type 1 (AT1R) and angiotensinogen (ATG) (Mehri et al, 2010; Lin et al, 2009). Several reports on association of ACE I/D polymorphism and T2DM with related cardiovascular and renal complication have been published but with controversial results. Whereas some have found that the D-allele is more common in T2DM and related complications (Baroudi et al, 2009; Naresh et al, 2009; Nikazamir et al, 2008), others have demonstrated no association of either allele with T2DM or related cardiovascular and renal disease (Sinorita et al, 2010; Jayapalan et al, 2010; Ramachandran et al, 2009)
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