**3.4 IL-12A, IL12B and IL-12RB2/ IL-23R**

IL-12A is a gene which encodes for IL-35 that is a subunit of the heterodimeric cytokines IL-12 (encoded by IL-12B) and IL-35 [49]. It binds to a heterodimeric IL-12 receptor (IL-12R) which consists of IL-12Rβ1 (encoded by IL-12 RB1) and IL-12Rβ2 (encoded by IL-12RB2) [50]. IL-12A gene variants (rs1780546 and rs17810458) were revealed to be associated with BD susceptibility in a Turkish cohort [23]. In a study with a Chinese cohort rs3212227/IL-12B genotype CC and C allele was found involved in the susceptibility to BD [51]. IL-23 is a member of the IL-12 cytokine family that plays important roles in the development process of the Th17 cells [52, 53]. The IL-23 receptor consists of two subunits encoded by the IL-23R and IL-12RB1 genes [54]. A meta-analysis of the association data (including a total of 2430 BD cases and 2660 controls) provided strong evidence for associations of the IL23R/IL12RB2 loci with BD [55]. The IL-23R/IL-12RB2 genes were associated with BD, in multiple reports with different populations including Japanese, Chinese, and Korean [56–58].

### **3.5 IL-17 and IL-18**

IL-17 is a pleiotropic inflammatory cytokine that plays a pivotal role in a variety of pathologic conditions by inducing numerous inflammatory molecules and the recruitment of neutrophils [59]. This cytokine is produced by CD + T helper, hematopoietic cells, Th17 cells and neutrophils and consists of a family of cytokines from IL-17A to IL-17F [60]. Jang et al. reported the allele and genotype frequencies of A126G SNP of IL-17 were significant differences between BD and controls [61]. The another genetic study in a Korean population, the IL17A rs8193036C > T variant was associated with the risk of intestinal BD [62]. In another study, the IL-17A gene rs2275913 polymorphism has been showed it might be associated with intestinal involvement in patients with BD [63]. IL-18 is a proinflammatory cytokine that mediates T-helper (Th)-1-polarized immune responses. Lee et al. found that IL-18 − 607 C/A promoter polymorphism was significantly associated with BD and also age at disease onset [64]. IL-18 gene −607 promoter site polymorphism was associated with patients with BD in Egyptian patients. Moreover, they found GG genotype at position −137 had a higher risk of developing ocular manifestations in patients with BD [65].
