The synergistic role of TNFA - 308G/A and IL10 - 1082A/G polymorphisms in ankylosing spondylitis

Abstract

Objective: Genetic polymorphisms of the cytokine genes could alter their protein expression, thus creating a genetic basis of dysregulated cytokine production and function, which render them as excellent candidates predisposing to autoimmune diseases. We investigated single nucleotide polymorphisms (SNPs) at TNFA - 308G/A and IL10 - 1082A/G locus to identify their involvement, separately or in combination, in determining susceptibility to ankylosing spondylitis (AS), as well as their functional connections with relevant serum cytokines and associations with disease characteristics.

Methods: Eighty-one AS patients and 215 healthy controls were genotyped by polymerase chain reaction-based method; 76 patients and sex-matched controls were also subjected to analysis of serum TNF-α and IL-10 levels by enzyme-linked immunosorbent assay.

Results: We identified the homozygous genotype GG of the TNFA-308 significantly more common in patients than controls; whereas the - 308 minor A-allele predicts a threefold decreased risk against developing AS and shows associations with milder radiographic spinal impairments and functional limitations. This protective effect was multiplied by fivefold in synergistic interaction with the homozygous - 1082AA genotype of the IL10 which acts as a modifying factor, since IL10 - 1082A/G SNPs by itself did not have a significant impact on AS genetic susceptibility. In comparison with controls, AS patients had significantly elevated mean serum TNF-α levels and decreased mean IL-10 concentrations not restricted to any particular genotype.

Conclusion: TNFA - 308 A-allele is essential for reducing susceptibility to AS, with a considerable synergistic protective effect of the combined TNF-α - 308 (GA/AA)/IL-10 - 1082AA genotypes. In addition, the presence of this variant allele is associated with more benign clinical phenotype of the disease. No conclusive statements on the functional relevance of both gene variants on cytokines production should be made.

Keywords: AS; Cytokine gene polymorphisms; Disease outcomes; IL-10; SNP; TNF-α.