TGF-β1 and IGF-I gene variations in type 1 diabetes microangiopathic complications

Abstract

Background: Growth factors are generally believed to have a perpetuating role in the development of diabetic complications, However there is ample of evidence of a protective or therapeutic potential for some of them. IGF-I, according to some reports, may contribute to complication development, although a protective role for IGF-I has been claimed for all late diabetic complications, making it an exception among growth factors. Transforming growth factor (TGF)-β1 as a pleiotropic cytokine is a key player in immunoregulation. Dysregulation of TGF-β1 in diabetes has been addressed as a leading event of kidney pathologies, while there is no similar pivotal role for TGF-β1 in diabetic retinopathy or neuropathy. An association study was conducted to evaluate the distinctive roles of TGF-β1 and IGF-I in T1DM microvascular complications by gene variation-based regulatory mechanisms that are operational in modulation of both in situ and systemic levels of the gene product.Methods: Two polymorphisms of the IGF-I gene at positions -383*C/T and -1089*C/T and two functional TGF-β1 gene polymorphisms, including codons 10 (+869*C/T) and 25 (+915*G/C) were examined in 248 British Caucasian T1DM patients and 113 healthy controls.Results: The distribution of IGF-1 gene polymorphisms did not reflect any significant association with different endpoints among the cases or different subgroups (complication triad) and controls. For TGF-β1 gene codon 25 polymorphism the low producer variant (allele C) were more frequent in cases than controls, which is compatible with the anti-inflammatory role of TGF-β1 and for codon 10 polymorphism the frequency of allele C was highest in retinopaths and, on the contrary and expectedly, nephropathy was more frequently accompanied by allele T (high producer). The frequency of allele G (high producer) of codon 25 polymorphism was slightly higher in the complication free group than in other subgroups.Conclusion: Although there were some differences in distribution of allele and genotype frequencies of TGF-β1 gene polymorphism in diabetes microvascular complications the differences were not statistically significant. Regarding IGF-1 our result firstly questions the functionality of the employed polymorphic marker and secondly may entail that the main regulator of IGF-I functionality resides elsewhere rather than the IGF-I gene itself, such as post-transcriptional regulation.