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: 2.39). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The renin angiotensin aldosterone system (RAAS) plays a vital role in regulating glucose metabolism and blood pressure, electrolyte and fluid homeostasis. The aim of this systematic review is to assess the association of the RAAS genes with diabetes mellitus (DM) and its complications of retinopathy, neuropathy and cardiovascular disease (CVD). The relevant English-language studies were identified using the key words of DM, type 1 diabetes mellitus (T1DM), T2DM, renin angiotensin aldosterone polymorphisms or genotypes and RAAS from the search engines of MEDLINE/PubMed, and Scopus from January 1, 1995 to July 30, 2014. Inclusion criteria for selecting relevant studies were reporting the role of RAAS gene variants in the pathogenesis of T1DM or T2DM, diabetic retinopathy (DR), diabetic neuropathy and cardiovascular complication of DM. The reviewers identified 204 studies of which 73 were eligible for inclusion in the present systematic review. The review indicates the angiotensinogen (AGT) M235T polymorphism might not affect the risk of DM. The role of angiotensin converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor gene (AT1R) A1166C polymorphisms in the pathogenesis of DM could not be established. Studies indicate the absence of an association between three polymorphisms of AGT M235T, ACE I/D and AT1R A1166C and DR in DM patients. A protective role for ACE II genotype against diabetic peripheral neuropathy has been suggested. Also, the ACE I/D polymorphism might be associated with the risk of CVD in DM patients. More studies with adequate sample size that investigate the influence of all RAAS gene variants together on the risk of DM and its complications are necessary to provide a more clear picture of the RAAS genes polymorphisms involvement in the pathogenesis of DM and its complications.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Podocyte injury and loss critically contribute to the pathogenesis of proteinuric kidney diseases including diabetic nephropathy. Deregulated lipid metabolism with disturbed free fatty acid (FFA) metabolism is a characteristic of metabolically unhealthy obesity and type 2 diabetes and likely contributes to end-stage kidney disease irrespective of the underlying kidney disease. In the current review, we summarize recent findings related to FFAs and altered renal FFA metabolism with a special focus on podocytes. We will outline the opposing effects of saturated and monounsaturated FFAs and a particular emphasis will be given to the underlying molecular mechanisms involving insulin resistance and endoplasmic reticulum homeostasis. Finally, recent data suggesting a critical role of renal FFA metabolism to adapt to an altered lipid environment will be discussed.
    Frontiers in Endocrinology 10/2014; 5:186. DOI:10.3389/fendo.2014.00186
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 gamma (PPAR gamma), acetyl-CoA carboxylase beta (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 epsilon 2 versus epsilon 3 was 1.49 (95 % CI 1.13-1.95) in T2DN. The progression of T2DN was related to the presence of the epsilon 2 allele and epsilon 2 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 PPAR gamma 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 epsilon 2 allele and ACACB rs2268388 C > T might act as promotion factors of nephropathy in type 2 diabetes, whereas PPAR gamma rs1801282 C > G is a promising candidate genetic variation for reducing susceptibility to T2DN.
    International Urology and Nephrology 09/2014; 47(1). DOI:10.1007/s11255-014-0843-6 · 1.29 Impact Factor