TGF-β1 and TSC-22 Gene Polymorphisms and Susceptibility to Microvascular Complications in Type 2 Diabetes

Abstract

Background/Aim: There is a strong evidence for the involvement of genetic factors in diabetic microvascular complications. The aim of our study was to investigate the role of molecular variants of the TGF-β1 (transforming growth factor beta 1) and the TSC-22 (transforming growth factor beta stimulated clone 22) genes in diabetic nephropathy and diabetic retinopathy in type 2 diabetes. Methods: A case-control study was conducted in 503 patients and 400 healthy subjects. DNA samples were genotyped by polymerase chain reaction and restriction fragment length polymorphism methods. Results: Among the patients, 245 had diabetic nephropathy, 195 had retinopathy, and 168 were free from complications. All subjects were genotyped for T869C and C –509T polymorphisms of the TGF-β1 gene and for –396 polymorphism of the TSC-22 gene. A significantly increased frequency of the CC genotype of the T869C polymorphism was observed in patients with nephropathy and retinopathy (33 and 48%, respectively, vs. 19 and 15%, respectively, in controls and patients free from complications). The frequency of the C allele was also higher (0.58 for nephropathy and 0.64 for retinopathy vs. 0.42 in controls). The G allele of the TSC-22 polymorphism was associated with an increased risk of diabetic nephropathy (frequency 0.15 vs. 0.07 and 0.06, respectively, in patients free from complications and controls). An interaction was observed between the G allele of the TSC-22 polymorphism and the C-allele of the TGF-β polymorphism. Conclusions: Our data suggest the association of TGF-β T869C gene polymorphism with an increased risk of nephropathy and retinopathy in type 2 diabetes patients. It interacts with the TSC-22 gene involved in the TGF-β signaling pathway, promoting the development of diabetic nephropathy.

Gene polymorphism of transforming growth factor-β1 in Egyptian patients with type 2 diabetes and diabetic nephropathy

“…While, significant associations were reported in Chinese [23], Caucasians Polish [22], and Mexicans [42], insignificant associations were reported in Asian Indians [43] and in Japanese [44]. Although the present study has no CC genotypes among selected DN patients, the significant increase in TC genotype in DN þ patients is in accordance with the meta-analysis study of Jia et al [45] on TGF-b1 T869C (codon 10) polymorphism.…”

“…In codon 25, statistically insignificant increase in GC genotype in patients than controls was demonstrated. Buraczynska et al [22] and Wong et al [23] studied TGF-b1 codon 10 polymorphism on Polish and Chinese populations, respectively. They reported different distribution of alleles, and genotypes compared with those in Egyptians.…”

The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels

“…An insufficient TGF-b response to diabetes may facilitate the progression of retinopathy; conversely, a robust response may decelerate its course and limit its severity. Our observations, together with reports that certain polymorphisms in the TGF-b 1 gene are associated with increased risk and severity of human diabetic retinopathy, 36,37 suggest a deserving venue for investigations to identify modulators of retinopathy.…”

Fenofibrate Inhibits Endothelin-1 Expression by Peroxisome Proliferator–Activated Receptor α–Dependent and Independent Mechanisms in Human Endothelial Cells

“…12 Genetic factors relate to diabetic microvascular complications and association of the transforming growth factor-β (TGFβ) T869C gene polymorphism with an increased risk of nephropathy and retinopathy in T2D has been observed. 13 The ET-1 promoter has binding sites for AP-1 and Smad transcription factors, which functionally cooperate through cAMP-response element binding protein/p300 to mediate TGFβ-induced transcriptional activation of the ET-1 gene.…”