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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[Show abstract][Hide abstract]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.
Full-text · Article · Jan 2014 · Journal of Diabetes
[Show abstract][Hide abstract]ABSTRACT: The rising prevalence of diabetes in South Asians has significant health and economic implications. South Asians are predisposed to the development of diabetes due to biologic causes which are exacerbated by lifestyle and environmental factors. Furthermore, they experience significant morbidity and mortality from complications of diabetes, most notably coronary artery disease, cerebrovascular disease, and chronic kidney disease. Therefore, understanding the pathophysiology and genetics of diabetes risk factors and its associated complications in South Asians is paramount to curbing the diabetes epidemic. With this understanding, the appropriate screening, preventative and therapeutic strategies can be implemented and further developed. In this review, we discuss in detail the biologic and lifestyle factors that predispose South Asians to diabetes and review the epidemiology and pathophysiology of microvascular and macrovascular complications of diabetes in South Asians. We also review the ongoing and completed diabetes prevention and management studies in South Asians.
No preview · Article · May 2014 · Current Cardiology Reports
[Show abstract][Hide abstract]ABSTRACT: Purpose:
Hyperlipidaemia has been identified as a risk factor for diabetic nephropathy via exacerbation of glomerular injury through the activation of multiple signaling pathways. This study's aim is to assess the associations between polymorphisms of genes involved in lipid metabolism, such as apolipoprotein E (ApoE), peroxisome proliferator-activated receptor γ (PPARγ), acetyl-CoA carboxylase β (ACACB), and type 2 diabetic nephropathy (T2DN).
A search of the MEDLINE and Web of Science databases was used to identify relevant studies, and allele or genotype frequencies were pooled using fixed- or random-effects models.
Forty-five studies were included in this meta-analysis, consisting of 10,920 type 2 diabetic patients with nephropathy and 16,203 type 2 diabetic patients without nephropathy. The OR for ApoE ε2 versus ε3 was 1.49 (95% CI 1.13-1.95) in T2DN. The progression of T2DN was related to the presence of the ε2 allele and ε2 carrier with ORs of 1.72 (95% CI 1.10-2.69) and 1.78 (95% CI 1.18-2.69), respectively. The rs1801282 C>G variant in PPARγ presented a significant association with decreased T2DN risk, both in the G allele and GC/GG genotype with ORs of 0.77 (95% CI 0.68-0.87) and 0.79 (95% CI 0.69-0.92), respectively. The T allele in rs2268388 within ACACB showed an increased risk for T2DN, exhibiting an OR of 1.35 (95% CI 1.12-1.63).
Our meta-analysis supports that the ApoE ε2 allele and ACACB rs2268388 C>T might act as promotion factors of nephropathy in type 2 diabetes, whereas PPARγ rs1801282 C>G is a promising candidate genetic variation for reducing susceptibility to T2DN.
No preview · Article · Sep 2014 · International Urology and Nephrology