Association of TGFβ1, TNFα, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians

Abstract

Background: Cytokines play an important role in the development of diabetic chronic renal insufficiency (CRI). Transforming growth factor β1 (TGF β1) induces renal hypertrophy and fibrosis, and cytokines like tumor necrosis factor-alpha (TNFα), chemoattractant protein-1 (MCP-1), and regulated upon activation and normal T cell expressed and secreted (RANTES) mediate macrophage infiltration into kidney. Over expression of these chemokines leads to glomerulosclerosis and interstitial fibrosis. The effect of MCP-1 and RANTES on kidney is conferred by their receptors i.e., chemokine receptor (CCR)-2 and CCR-5 respectively. We tested association of nine single nucleotide polymorphisms (SNPs) from TGFβ1, TNFα, CCR2 and CCR5 genes among individuals with type-2 diabetes with and without renal insufficiency.

Resequencing of the CCL5 and CCR5 genes and investigation of variants for association with diabetic nephropathy

“…7 CCL5 and CCR5 have received considerable attention as candidate genes for DN, although these studies have focused on selected variants with inconsistent findings. [8][9][10][11][12][13][14][15] The CCL5 gene locus has been assigned to 17q11.2-q12, 16 and the CCR5 gene is located on chromosome 3p21. 17 Coding regions, intron-exon boundaries, untranslated and flanking regions of the CCL5 and CCR5 genes have been comprehensively screened to identify polymorphisms, and a robust case-control study was performed to assess the association between common haplotype tagging or functional variants and DN in a Caucasian population with type 1 diabetes.…”

“…Twelve haplotypes were observed and five htSNPs selected, including CCR5_rs333, a 32-bp deletion reported to confer resistance to HIV. 19 One additional SNP (CCR5_rs1799987) was selected for genotyping on the basis of previous association with DN, [8][9][10][11][12][13] as well as putative functionality. 19 The selected SNPs were genotyped in an Irish casecontrol collection of sufficient size to provide approximately 80% power to detect an odds ratio (OR) of 1.6, with an MAF of 10%.…”

“…Investigations in Japanese and Asian Indian populations have suggested an association between CCR5_rs1799987 (alias 59029G4A) and DN and renal insufficiency in the type 2 diabetic population. 8,[11][12][13] CCR5_rs1799987 is a putatively functional variant, located in the promoter region, which influences expression of the CCR5 protein. 19 As CCR5_rs1799987 is the most frequently investigated SNP in previous publications, a sample size calculation was performed for this variant.…”

“…14,15 The published association studies on CCL5 and CCR5 performed to date have focused on one or two selected variants in the gene, which were often chosen on the basis of function. A meta-analysis was performed to include data from these reports, [8][9][10][11][12][13][14] which investigated three loci relevant to our study: CCL5_rs2107538 (pooled OR 0.99; 95% CI 0.80-1.23; P¼0.94), CCR5_rs1799987 (pooled OR 0.96; 95% CI 0.78-1.17; P¼0.66) and CCR5_rs333 (pooled OR 0.96; 95% CI 0.78-1.19; P¼0.73). It should be noted that studies investigating CCR5_rs1799987 exhibit heterogeneity even after the exclusion of the data reported by Ahluwalia et al, 13 which showed very marked deviations from Hardy-Weinberg equilibrium.…”

Association of Transforming Growth Factor Beta-1 (TGF-β1) Genetic Variation with Type 2 Diabetes and End Stage Renal Disease in Two Large Population Samples from North India

“…The exonic (g.869T > C) and promoter (g.-509C > T) polymorphisms have been associated with DN traits (Coll et al, 2004;Khalil et al, 2005;Prasad et al, 2007). As the public health impact of DN is expected to grow in the years to come due to the increasing prevalence of diabetes (Vinod, 2012) and moreover keeping in view the role of genetic predisposition for the development of these diseases, the present study aimed to determine the association of TGF-b1 g.869T > C and g.-509C > T polymorphisms in T2D and ESRD cases derived from T2D in the two geographically and ethnically different populations of North India.…”