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

Abstract

Geographic and ethnic differences impart an immense influence on the genetic susceptibility to Type 2 diabetes (T2D) and diabetic nephropathy (DN). Transforming growth factor-beta1 (TGF-b1), a ubiquitously expressed pro-fibrotic cytokine plays a pivotal role in mediating the hypertrophic and fibrotic manifestations of DN. The present study is aimed to study the association of TGF-b1 g.869T > C (rs1800470) and g.-509C > T (rs1800469) polymorphism in T2D and end stage renal disease (ESRD) cases from the two geographically and ethnically different populations from North India. A total of 1313 samples comprising 776 samples from Punjab (204 with ESRD, 257 without ESRD, and 315 healthy controls) and 537 samples from Jammu and Kashmir (150 with ESRD, 187 without ESRD, and 200 controls) were genotyped for TGF-b1 (rs1800470 and rs1800469) using ARMS-PCR. The CC genotype of rs1800470 increased ESRD risk by 3.1-4.5-fold in both populations. However, for rs1800469, the TT genotype provided 5.5-fold risk towards ESRD cases from Jammu and Kashmir and no risk for the cases from Punjab. The haplotype C-T conferred nearly a 2-3-fold risk towards T2D and ESRD and diplotype CC-CT conferred a 4-fold risk towards ESRD. Our results conclude that TGF-b1 (rs1800470) may increase the risk of both ESRD and T2D in both populations, but TGF-b1 (rs1800469) provided risk for only ESRD in the population of Jammu and Kashmir. The present study is one of the large sample sized genetic association studies of T2D and ESRD from Indian population and adds to the scholarship on global health omics.

Type 2 diabetes–associated polymorphisms correlate with SIRT1 and TGF‐β1 gene expression

“…This study shows that the rs3758391 associated with T2D, breast cancer, autoimmune thyroid disease, lupus erythematosus, and depression disorders, among others (Consiglio et al., ; Hathaway et al., ; Kovanen, Donner, & Partonen, ; Rizk et al., ; Sarumaru et al., ) and the rs1800470 associated with T2D, diabetic nephropathy, acute coronary syndrome, and asthma (Dragicevic, Petrovic‐Stanojevic, & Nikolic, ; Fragoso et al., ; Raina et al., ; Yang et al., ) are correlated with gene expression levels of SIRT1 and TGF‐β1 , respectively, in peripheral blood from adults. However, rs3758391, rs932658 (in LD with rs3758391), and rs1800470 are not located in DNA‐protein binding sites in the cell line BxPC‐3.…”

“…The T allele of rs1800470 has been previously associated with diabetic nephropathy, high serum cholesterol, and TG in Mexican, Asian, and some Indian groups (Raina et al., ; Valladares‐Salgado et al., ; Zhou, Jiang, Qin, & Drummen, ). This study demonstrates that the rs1800470 risk allele is related to the increase of the transcription of the gene.…”

“…To date, the functional and molecular mechanisms of only a fraction of these disease‐associated polymorphisms is known (Meigs, ). Here, we study two SNPs associated with T2D and diabetic nephropathy in the Mexican population, which have been previously reported by our group and others (rs3758391 [T/C] and the rs1800470 [C/T]) to explore the functional mechanism of these SNPs (Cruz et al., 2010, ; Raina et al., ).…”

“…T2D is a multifactorial disease with environmental and genetic components, which have different effect sizes with complex and still not well comprehended interactions (Barroso & McCarthy, ). In particular, genome‐wide association studies (GWAS) have identified more than 400 single‐nucleotide polymorphisms (SNPs) associated with T2D and/or the severity of comorbidities such as cardiovascular disease, hypertension, retinopathy, nephropathy, and diabetic foot, among others (Barroso & McCarthy, ; Mahajan et al., ; Raina et al., ; Scott et al., ). These studies have revealed an important variability in association strength and, in several cases, its association is population‐dependent where ancestry plays a critical role (Liu et al., ; Parra et al., ).…”

Osthole protects against inflammation in a rat model of chronic kidney failure via suppression of nuclear factor-κB, transforming growth factor-β1 and activation of phosphoinositide 3-kinase/protein kinase B/nuclear factor (erythroid-derived 2)-like 2 signaling

“…TGF-β1, transforming growth factor-β1; CRF, chronic renal failure; Con, control group; Con-Ost, control + osthole group; Ost, CRF + osthole group. may involve TGF-β1 (20,21). Cytokines may be involved in promoting or resisting renal interstitial fibrosis (22).…”