ACACβ gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes.

Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Molecular and Cellular Biochemistry (Impact Factor: 2.33). 10/2012; DOI: 10.1007/s11010-012-1460-2
Source: PubMed

ABSTRACT Patients with type 2 diabetes (T2DM) are usually obese and concurrent obesity results into activation of the renin-angiotensin-system (RAS) which is a risk factor for diabetic nephropathy (DN). Gene-gene interaction between acetyl-coenzymeA carboxylase beta (ACACβ) gene, which is involved in fatty acid metabolism and angiotensin II receptors (AGTR1) gene, which mediates RAS proteins actions on renal tissue, polymorphism with DN have not been studied earlier. The present study was designed with the aim to examine the association of an ACACβ (rs2268388) and AGTR1 (rs5186) gene polymorphism with the risk of DN in Asian Indians. 1,158 patients with T2DM belonging to two independently ascertained North Indian and one South Indian cohorts were genotyped for ACACβ (rs2268388) and AGTR1 (rs5186) polymorphism using real time PCR-based Taq-man assay and PCR-RFLP assays. In all the three cohorts, a significantly higher frequency of T allele and TT genotypes of ACACβ and C allele and CC genotypes of AGTR1 were found in patients with DN as compared to patients without nephropathy. Further, T allele of ACACβ and C allele of AGTR1 were found to be significantly associated with proteinuria, a hallmark of DN. We also found significant epistatic interactions between these two genes. TT genotypes of ACACβ gene and CC genotype of AGTR1 gene confers the risk of DN and both genes had significant epistatic interaction in Asian Indian patients with T2DM.

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    ABSTRACT: Diabetic nephropathy (DN), the leading cause of end-stage renal disease worldwide, might have a genetic component. We investigated variations in a set of genes with susceptibility to DN in north Indian population. We selected four genes (HFE, ELMO1, SLC12A3 and CCR5), based on reported association with type 2 diabetes and nephropathy. A total of 417 diabetic subjects: 215 without kidney disease (DM), 202 with DN and 197 healthy controls (HC) were evaluated for variation in HFE (845 G>A and 187G>C) SLC12A3 (g.34372G>A), CCR5 (59029A>G) and ELMO1 (+9170 G>A) genes. Polymorphism analysis was performed by PCR-RFLP and Taqman allele discrimination assay. A significant difference was found in genotype and allelic frequency in SLC12A3 (g.34372G>A) between diabetic and HC (p<0.03). No difference in SLC12A3 g.34372G>A (AA+GA) genotype was noted between diabetics with and without nephropathy. CCR5 59029AA genotype and A allele were significantly more frequent in diabetics as compared to HC (p=0.01, 0.03) and in DN as compared to DM (p=0.002,0.01). In ELMO1 (+9170 G>A), GG genotype frequency was higher in diabetic group as compared to HC. There was no difference in HFE-845 G>A and HFE-187G>C frequency between the groups. This study shows that the CCR5 AA genotype is over-represented in subjects with kidney disease due to type 2 diabetes. The CCR5 59029G>A and ELMO1 (+9170 G>A) loci are more frequent, and SLC12A3 34372 AA genotype is associated with reduced risk of diabetes.
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