**4.3 MEFV**

The Mediterranean fever (MEFV) protein also named pyrin is an is an significant regulator of innate immunity and the inflammatory response to IL-1β and IFN-γ. Some clinical findings and geographic distribution of FMF and BD seem to be similar [80]. Touitou et al. who first suggested a possible implication of MEFV mutations in BD, reported higher frequencies of four mutations such as M694V, V726A, E148Q, and L110P mutations [81]. The MEFV SNPs rs61752717 Met694Val, rs28940580 Met680Ile, and rs3743930 Glu148Gln were reported conferred risk to both of FMF and BD [80, 82–84].

#### **4.4 IRF1 and IRF8**

IRF-1 is originally identified to be a regulator of the interferon (IFN)–β gene family. It plays an important role in various biologic functions such as innate immunity to viral infection, lymphocyte development, macrophage cytotoxicity, induction of apoptosis and tumor suppression [85, 86]. A study by Lee et al. showed that a significant association between BD and IRF-1 gene polymorphisms (-415 C/A, -410 A/G, and -300 A/G, and 3'-untranslated region (UTR) A/G) [87]. Interferon Regulatory Factor (IRF) 8 is a transcription factor of a member of Interferon (IFN) Regulatory Factor (IRF) family that it regulates expression of type I IFN stimulated genes and the development and function of a variety of immune cells [88, 89]. The rs17445836 and rs11642873 polymorphisms of the IRF8 gene were associated with BD and these SNPs appeared to regulate IRF8 expression and cytokine production in a Chinese cohort [90]. The other SNPs (rs11117433, rs142105922 and rs7203487) of the IRF8 gene were reported BD-associated in multiple cohorts including Turkish, Iranian, and Japanese populations [91].

#### **4.5 TNFAIP3**

TNFAIP3 gene encodes A20 protein, which is a key regulator of the nuclear factor (NF)-κB signaling pathway, toll-like receptor (TLR), interleukin 1 receptor (IL1R), and nucleotide-binding oligomerization domain containing 2 (NOD2) [92]. A genetic linked between the TNFAIP3 gene SNPs (rs9494885, rs10499194 and rs7753873) and BD was reported in Chinese BD patients [93].

#### **4.6 Toll-like receptors**

Toll-like receptor (TLR) proteins are a family receptors that recognize pathogen molecules and have a critical role in both innate and adaptive immune systems [94]. TLRs are thought to be one of the links between infection and autoinflammatory or autoimmune disease [95]. The TLR2 rs2289318 CC genotype and rs3804099 CT genotype were significantly associated with ocular BD in a Chinese population [96]. The associations of the TLR4 gene with BD have been found to be contradictory in different studies. It was not found an association between TLR4 gene polymorphisms and BD in Italian and Chinese patients [97, 98]. Horie et al. showed that the TAGCGGTAA haplotype of TLR4 gene was significantly associated with BD susceptibility and BD arthritis in a Korean cohort [99]. A Japanese study indicated that the TLR4 gene may confer susceptibility to BD [100]. Fernández et al. revealed the rs2407992 and the rs5744067 of TLR8 were associated with susceptibility to BD in Spanish patients [101]. An Asian study revealed a significant association between the TLR7 rs5743733 and rs3853839 and BD and it showed also an association of TLR9 rs352140 with BD [102].

#### **4.7 GIMAP**

The GIMAP (GTPase of the immune associated nucleotide binding protein) gene family have been suggested as being involved in different aspects of the immune system in different species. These events appear to be associated with cell regeneration and proliferation and apoptosis [103]. The SNPs in GIMAP1 (rs2286900), GIMAP2 (rs10266069 and rs10256482), and GIMAP4 (rs1916012, rs1522596, and rs1608157) were associated with BD in a study of Korean and Japanese populations, but they were not found to be associated in a study with European cohort [104].

## **4.8 NOD1 and NOD2**

Nod-like receptors (NLRs) are a member of pattern-recognition receptor molecules (PRRs) can capable to sense several pathogens or endogenous danger signals [105]. In a Chinese study, the C allele (major) of the NOD1 SNP rs2075818 was associated with BD susceptibility [21]. In a recent study indicated that the CC genotype of rs2075818 (NOD1 G/C) increased the risk of BD by 3.780-fold and the AA genotype of rs2075820 (NOD1 G/A) was increased the risk of cardiovascular involvement in BD 4.286-fold. In addition, they did not find the NOD2 gene variants (R334Q and R334W) in nor the BD patients and neither control groups [106]. Multiple reports have demonstrated that a Crohn's disease-associated polymorphism, Arg702Trp of the NOD2 rs2066844 was protective to BD [107, 108].
