2.2.1. Cytokines and Cytokine Receptors

A significant number of RA-associated genetic variants have been identified in the interleukins (ILs) and their receptor genes. Interleukins are cytokines that stimulate hematopoietic cell development and T- and B-lymphocyte differentiation. There are seven interleukin families characterised by significant variability in both ligand forms and receptors. The key mediator of inflammation, IL1, is represented by two isoforms and is combined with another nine interleukins in one family. Its expression is affected by the –511A/G (rs16944) polymorphism in the promoter (associated with RA in Caucasians) and the +3953C/T polymorphism in exon 5 (RA-associated in some Asian populations). According to meta-analyses, RA-associated alleles in Caucasians include –174G/C and –572G/C of the *IL6* gene, rs1800896 in the *IL10* gene, rs13151961 and rs6822844 located near the *IL2* and *IL21* genes, rs7530511 and rs11209026 in the *IL23R* gene, and some others. A significant number of RA-associated polymorphic loci included in the meta-analyses are unique to Asian populations. The polymorphism found at rs1946518 of the *IL18* gene is found in Egyptian populations, and the polymorphism found at rs549908 is found in the Taiwanese population. Thus the candidate genes for assessing genetic RA predisposition need to be thoroughly selected [19–22].

Another candidate gene is *IL2RA*, which encodes the interleukin 2 (IL2) receptor α-subunit. The rs12722495 polymorphism of this gene correlates with its mRNA and protein expression in stimulated monocytes, naive T-cells, and memory T-cells [6]. Additionally, according to a meta-analysis of 37 studies, a minor allele A of the rs1343151 polymorphism in the IL23R gene, which encodes the receptor for interleukin 23, is associated with a risk of developing RA [23].

#### 2.2.2. Chemokines and Chemokine Receptors

Changes in the *CCR6* gene can affect the development of RA. This gene encodes the chemokine receptor, which is the surface marker of Th17 cells. Dinucleotide polymorphism rs3093024 in the 5 regulatory sequence of CCR6 binds nuclear proteins. This polymorphism is associated with expression levels of the chemokine receptor and increased plasma concentration of IL17 cytokine in RA patients. The role of the CCR6 receptor in RA development appears to be more significant than previously known due to its expression on different subtypes of T-cells involved in the regulation of inflammation. According to a meta-analysis, rs3093024 and several other SNPs (single nucleotide polymorphism) in *CCR6* are associated with RA in European and Asian populations [6,24]. At the same time, a 32-bp deletion in another chemokine receptor gene, *CCR5,* has a protective effect, according to a case–control study in Brazil with samples of 740 RA patients and 676 controls [25].

The *CCL2* gene encodes the chemoattractant protein, which recruits monocytes and T-cells during inflammation. A meta-analysis of the functionally significant 2518A/G polymorphism of this gene promoter on chromosome 17 was performed. This polymorphism was studied for associations with various autoimmune diseases (systemic lupus erythematosus, RA, systemic sclerosis, nephropathy with Ig-A, Crohn's disease) in different populations. The unfavourable allele A showed the most pronounced association with RA in Asian populations, as well as with Crohn's disease in Europeans [26].
