POLYMORPHISMS OF THE PRO-INFLAMMATORY CYTOKINE GENES IL6 (C174G) AND TNF-Α (G308A) IN THE PATHOGENESIS OF DIABETIC FOOT SYNDROME IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Abstract

Background. Chronic low-grade inflammation is a central mechanism of vascular complications in diabetes mellitus, and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) are key mediators of the impaired wound healing that characterizes the diabetic foot syndrome (DFS). Functional single-nucleotide polymorphisms in their genes may modify cytokine expression and disease susceptibility. Aim. To determine the distribution of the IL6 C174G (rs1800795) and TNF-α G308A (rs1800629) polymorphisms in patients with DFS and controls, and to assess their association with DFS and with its neuropathic and neuroischemic forms. Materials and methods. Both polymorphisms were genotyped by polymerase chain reaction in 96 patients with type 2 diabetes and DFS (35 neuropathic, 61 neuroischemic) and in 83 control subjects. Allele and genotype frequencies were compared using the χ² test and the odds ratio (OR) with 95 % confidence intervals (CI), and conformity to Hardy–Weinberg equilibrium was verified. Results. Genotype distributions conformed to Hardy–Weinberg equilibrium. For IL6 C174G, the minor G allele and the heterozygous C/G genotype were more frequent in DFS patients than in controls (G allele 16.7 % vs 12.0 %, OR = 1.5; C/G 25.0 % vs 16.9 %, OR = 1.6), whereas the C allele and C/C genotype were protective. For TNF-α G308A, the minor A allele and the heterozygous G/A genotype increased DFS risk (A allele 9.9 % vs 5.4 %, OR = 1.9; G/A 19.8 % vs 10.8 %, OR = 2.0), and the association of the G/A genotype reached significance in the neuropathic form (OR = 2.8, 95 % CI 1.05–7.73). Carriage of the risk genotypes accompanied higher leukocyte counts and a higher leukocyte intoxication index. Conclusion. The G allele of IL6 C174G and the A allele of TNF-α G308A, together with their heterozygous genotypes, are associated with susceptibility to DFS, supporting the involvement of genetically determined pro-inflammatory cytokine activity in the pathogenesis of the syndrome.