Polymorphisms in the Genes Encoding TGF-β1, TNF-α, and IL-6 Show Association with Type 1 Diabetes Mellitus in the Slovak Population

Abstract

Numerous cytokines have been shown to participate in the pathogenesis of type 1 diabetes (T1D). As gene polymorphisms can influence cytokine production or function, they may potentially contribute to genetic predisposition to the disease. The aim of this study was therefore to investigate the role of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine and cytokine receptor genes in genetic susceptibility to T1D. Polymerase chain reaction with sequence-specific primers was used to genotype cytokine SNPs and HLA-DRB1 alleles in 151 diabetics and 140 healthy individuals of Slovak origin. Univariate analysis showed that transforming growth factor (TGF)-beta1 codon 10 TT homozygotes were significantly more susceptible to developing T1D than C allele carriers (P (c) = 0.0066, OR = 2.46). Furthermore, tumor necrosis factor (TNF)-alpha -308 A allele carriers were also significantly overrepresented among the diabetics (P (c) = 0.0031, OR = 2.62); however, the association of the -308 A allele with T1D might be due to its strong linkage disequilibrium with the susceptibility allele HLA-DRB1*0301. An association was also found with interleukin (IL)-6 -174 G/C and nt565 G/A SNPs; however, its significance was lost when statistical correction was applied. These data suggest that the TGF-beta1 codon 10 SNP is among numerous genetic variations with small individual effects on T1D development. Moreover, a possible role of TNF-alpha and IL-6 SNPs cannot be ruled out, although their association with T1D was due to strong LD with the HLA class II susceptibility allele or did not withstand statistical correction, respectively.

Tumor necrosis factor–associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes

“…An evaluation of the multiple polymorphisms in the TNF region revealed that these are in good fit with Hardy-Weinberg equilibrium in this population. In addition to the positive association of TNF Ϫ238G and/or TNF Ϫ308A alleles with T1D, as reported in other populations [37,45,50,51], we also observed a significant positive association of the TNFa5 allele in the North Indian population. The fact that TNF Ϫ308A allele is a "high expressor" allele [35,52] explains the immunological basis of its association with the inflammatory stage of pathogenesis of T1D to some extent.…”

“…These results highlight possible populationbased variations in TNF association with T1D, although other factors that include discordance in study design, statistical evaluations, sample size, and methods of genotyping employed in different studies can also affect ethnic discrepancies. It has been suggested that the observed TNF association may indeed be caused by their LD with T1D-associated HLA class II alleles or haplotypes [47][48][49][50].…”

Asociación del polimorfi smo TNF-alpha -308 G/A con los cambios metabólicos secundarios a una dieta hipocalórica rica en proteínas/baja en hidratos de carbono versus una dieta hipocalórica estándar

“…In our study the frequencies of genotypes did not markedly differ from data previously reported in the literature (18)(19)(20). Contrasting with numerous reports on the frequencies of -308 G/A SNP and association with body adiposity and metabolic disturb- Table I.…”

TNF-alpha-238, -308 polymorphisms, and diabetes

“…Previous studies have reported strong linkage disequilibriums between HLA DR3, HLA-DRB1*0301 alleles, and TNF-alpha-308 polymorphism [1,4], indicating that this significant association of TNF-alpha-308 polymorphism may not be independent. TNF-alpha-308 polymorphism might be only a participant in the whole genetic pathopoiesis of T1DM.…”