Polymorphisms within Genes Involved in Regulation of the NF-κB Pathway in Patients with Rheumatoid Arthritis.

Genes involved in regulation of the nuclear factor-κB (NF-κB)-pathway are suggested to play a role in pathogenesis of rheumatoid arthritis (RA). In the present study, genetic polymorphisms of TLR2 , TLR4 , TLR9 and NF-κB1 genes were investigated to assess their associations with RA susceptibility, progression and response to anti-TNF-α therapy. A group of 110 RA patients and 126 healthy individuals were genotyped for TLR2 (rs111200466), TLR4 (rs4986790, rs4986791), TLR9 (rs5743836, rs187084) and NF-κB1 (rs28362491) alleles. The presence of the TLR9 -1486 T variant ( p < 0.0001) and its homozygosity ( p < 0.0001) were found to be associated with disease susceptibility. The TLR9 -1237 C allele was associated with predisposition to RA in females only ( p = 0.005). Moreover, the TLR4 rs4986791 G (rs4986790 T ) alleles were more frequently detected among patients with the stage IV disease ( p = 0.045), and were associated with more effective response to anti-TNF-α therapy ( p = 0.012). More efficient response to anti-TNF-α treatment was also observed in patients with del within the NF-κB1 gene ( p = 0.047), while for the TLR9 -1486 T homozygotes, the treatment was ineffective ( p = 0.018). TLR polymorphisms affect disease susceptibility and response to therapy with TNF-α inhibitors in RA patients of Caucasian origin.