GENETIC POLYMORPHISMS PREDISPOSING TO MUSCULOSKELETAL INFECTIONS

Abstract

It is known that wide variability exists among patients in the susceptibility to and outcome from infection. Polymorphisms in genes coding for proteins involved in the response to bacterial pathogens as tumor necrosis factor-alpha(TNF-a), interleukin (IL)-1alpha, IL-1beta, IL-1 receptor agonist, IL-6, IL-10 can influence the amount or function of the protein produced in response to bacterial stimuli. These genetic polymorphisms may influence the susceptibility to and outcome from infection.

The aim of the study was to investigate whether genetic variation in genes coding for components of the innate immune response might be a critical determinant of the inflammatory response and the risk for and outcome from severe bacterial infection in individuals with musculoskeletal infections. The relationship between single nucleotide polymorphisms (SNPs) in the above mentioned genes and susceptibility to infection was evaluated.

Forty patients with musculoskeletal infections hospitalised at the Orthopaedic Clinic of University Hospital of Larissa, as well as 80 healthy controls were included in the study. Genomic DNA was isolated from peripheral blood from all cases and controls and was extracted according to standard procedures. The following genes with their polymorphic positions were studied: IL 1α (IL 1α promoter −889), IL 1β (IL 1β promoter −511, pos. +3962), IL 1R (IL 1R pos. pst1 1970), IL 1RA (IL 1RA pos. mspa1 11100), IL 4Rα (IL 4Rα pos. +1902), IL 12 (IL 12 promoter −1188), TGF-β (TGF-β exon 1 codon 10, codon 25), TNF-α (TNF-α promoter −308, −238), IL 2 (IL 2 promoter −330, pos. +166), IL 4 (IL 4 promoter −1098, −590, −33), IL 6 (IL 6 promoter −174, pos. +nt 565) and IL 10 (IL 10 promoter −1082, −819, −592). Genotype distribution and allele frequencies in patients and controls were evaluated.

There was a significant difference in genotype and allele frequency of IL-1a (T/C −889) p=0.000 (CC, TC) between patients and the control group. Moreover, 2 SNPs of interleukin 4 [IL-4 (T/G −1098) p=0.000 (GG, GT) p=0.009 (TT) and IL-4 (T/C-590) p=0.000 (CC, CT) p=0.006 (TT)] showed significant genotypic and allelic differences between the two groups. Finally, 2 SNPs of interleukin 6 [IL-6 (G/C-174) p=0.000 (CC) p=0.014 (GG), IL-6 G/A nt565) p=0.000 (AA,GA,GG)] and TNF-a [(G/A-308) p=0.034 (AG)] showed significant differences in genotype and allele frequencies between patients and the control group.

We observed, for the first time, significant differences in genotype and allele frequencies of TNF-a (G/A-308), IL-1a (T/C -889), IL-4 (T/G -1098), IL-4 (T/C-590), IL-6 (G/C-174) and IL-6 G/A (nt565) in patients with musculoskeletal infections, a fact which points towards the involvement of cytokine gene polymorphisms in the pathogenesis of infection.