**3. Interleukin (IL) family genes**

#### **3.1 IL-1 gene family**

IL-1 gene family is composed of IL-1α, IL-1β, and IL-1Ra [32]. Interleukin-1α and -1β, are pleiotropic cytokines with primarily proinflammatory effects, which induce acute phase responses, activate endothelial cells, and lead to expression of adhesion molecules and coagulation factors [33]. IL-1Ra acts as an antagonist of IL-1 by blocking the IL-1 receptor [34]. Previous studies have shown that the IL-1α (-889) C allele is significantly associated with BD risk [35, 36]. Alayli et al. also reported that the frequency of IL-1β (−511) CC genotype is significantly higher in BD patients compared to controls [35]. In another study showed that IL-1Ra mspa1l 1100 CT and IL-1Ra mspa1l 1100 TT promoter polymorphisms could be confer susceptibility to BD in Turkish population [37]. Barış et al. found IL-1RN2 gene polymorphism was correlated with the presence of articular involvement and the IL-1β gene polymorphism was correlated with the presence of an ocular lesion [38].

#### **3.2 IL-4**

Interleukin-4 (IL-4) is a key cytokine secreted by Th2 lymphocytes. It has cytotoxic, anti-tumor effects, inhibits induction of nitric oxide synthase, and also has role in chemotaxis, formation of endothelial cell adhesion molecules and hematopoiesis [39]. IL-4 gene 70 bp VNTR polymorphism was first reported to be associated with BD in the Turkey. The P1 allele of the IL-4 gene 70 bp VNTR polymorphism was found to constitute a risk for developing BD in a Turkish population. In the same study, P2P2 genotype was associated deep venous thrombosis and ocular involvement in the BD patients [40]. The IL-4 -1098 G, IL-4 -590 T alleles and IL-4 TTC haplotypes were showed more common in the patients with BD when compared with healthy controls in an another Turkish cohort. They also demonstrated that IL-4Rα (+1902) gene polymorphism was associated with the Pathergy test positivity in BD patients [41].

#### **3.3 IL-10**

IL-10 is an anti-inflammatory cytokine, which is secreted by T lymphocytes (mainly Th2 subsets), B lymphocytes, NK cells, monocytes, and macrophages, plays critical roles in modulating immune response and preventing inflammatory and autoimmune pathologies [42]. IL-10 may inhibit the antigen-presenting process by downregulating the expression of HLA molecules on the surface of a cell and suppressing the expression of multiple proinflammatory cytokines, such as TNF-α, IL-1, IL-6, and IL-8 [43]. The first reported SNP of the IL10 gene was rs1800871 that found to be an association with BD in the UK and Middle Eastern cohorts [44].

The -1082A > G (rs1800896), −819 T > C (rs1800871), and -592A > C (rs1800872) SNPs of IL-10 gene were found to be association with BD susceptibility in different populations including Chinese, Japanese, Korean and Iranian [45–48].
