2.2.3. Components of Intracellular Pathways That Regulate Proliferation

A number of RA candidate genes are involved in the NF-κB signalling pathway. One of the *CD40* alleles, which is also an RA candidate gene, is associated with increased expression of CD40 molecules on the surface of B-cells and intensified NF-κB signalling. Another RA candidate gene is *TNFAIP3*, which encodes a component of the NF-κB signalling pathway—the A20 ubiquitin-modifying enzyme. These independent gene polymorphisms associated with RA were identified by meta-analyses. One of them—the TT > A substitution located a 42-kb distance from the promoter—reduces the binding avidity of NF-κB signalling pathway transcription factors, leading to decreased TNFAIP3 and A20 protein expression. Another possible SNP is the replacement of phenylalanine with cysteine at the 127 position, which disturbs the A20 function. Interestingly, A20 is often inactivated due to somatic

mutations in B-cell lymphoma. The *TNFAIP3* gene is located in the 6q23 region. Besides the *TNFAIP3* gene, this region contains plenty of autoimmune disease candidate genes: *IL20RA*, *IFNGR*, *OLIG3* and others [27,28].

Involved in the JAK/STAT pathway, the *STAT4* gene was identified as a candidate gene for RA and other autoimmune diseases as a result of GWAS. *STAT4* encodes the signal transducer and activator of transcription protein 4 (STAT4). The rs7574865 polymorphism of the *STAT4* gene is associated with RA in different ethnic populations. The STAT family proteins act as JAK-activated transcription factors and are important in many cytokines signalling pathways, primarily the interferon pathways. Detected unfavourable rs7574865 alleles were associated with STAT4 overexpression and increased production of interferon-α [29]. STAT4 transcription factors are also involved in the regulation of proinflammatory helper T-cell (Th1, Th2, Th17) differentiation, of which Th1 and Th17 are directly involved in autoimmune reactions [6,19,29].
