**2. HLA and HLA-related genes**

## **2.1 HLA**

The MHC, also known in humans as the human leukocyte antigen (HLA) region encodes several molecules that play key roles in the immune system [7]. A strong

association was established between the HLA regions and autoimmune disorders. Among them, HLA-B51 has been shown to be the strongest risk allele for BD in multiple studies and in different ethnic populations [6, 8–11]. Several other HLA class I and class II alleles including HLA-A26, HLA-B15, HLA-B5701, HLA-B2702, HLA-B3901, HLA-B52, HLA-B56, HLA-DRB104, and HLA-DRB107 have been also associated with BD in different populations [12–15]. The several HLA alleles including HLA-A03, -B15, -B35, -B49, -B58 were reported BD-protective [1, 16, 17]. In addition to susceptibility, HLA alleles were also associated with reflect clinical outcomes of BD. The HLA-A26:01 was associated with poor visual prognosis and high incidence of posterior uveitis in previous studies [15, 18]. There were significant associations found between clinical manifestations of BD and some HLA alleles such as HLA-A26:01 with uveitis, HLA-A\*02:07 with skin lesions and arthritis, and HLA-A\*30:04 with vascular lesions, genital ulcers, and positive pathergy test [17]. These findings indicate that HLA alleles may be associated clinical manifestations and prognosis and the specific HLA alleles are can be used as genetic markers for diagnostic or prognostic classification of BD patients.

## **2.2 CIITA**

The HLA class II transactivator gene (CIITA), encodes an important transcription factor that regulates the MHC class II genes, IL-4, IL-10 and other immune-mediating genes [19]. CIITA is implicated in various autoimmune and autoinflammatory diseases [20]. In a recent study of a Chinese Han population, the GG genotype and G allele of the CIITA gene (rs12932187) were correlated with risk factor for BD, and the GG carriers had a higher expression of the CIITA gene [21].

#### **2.3 ERAP1**

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an essential enzyme to optimizing the length of peptides to bind with MHC-class I molecules by trimming their N-terminal in the ER [22]. The association between ERAP1 and BD was first reported in a Turkish population. The rs10050860 and rs17482078 SNPs of the ERAP1 gene were found to confer risk to BD in Turkish population [23]. Zhang et al. reported the rs1065407 and rs10050860 polymorphisms might be associated with increased risk of BD in a Chinese cohort [24]. Sousa et al. studied in an Iranian cohort and reported that rs10050860 and rs13154629 of ERAP1 might contribute to the genetic susceptibility of BD [25]. A functional study indicated that the expression of ERAP1 was found to be significantly lower in active BD patients. The patients carrying AA genotype of rs1065407 and CC genotype of the rs10050860, respectively, were found a higher expression level of the ERAP1 gene than the patients carrying AC or CC and CT or TT genotypes of the SNPs, respectively, in response to lipopolysaccharide stimulation [24, 26].

#### **2.4 MICA**

The major histocompatibility complex class I chain related gene A (MICA) is a gene that functions in immune activation under cellular stress conditions, such as infections, tissue injury, pro-inflammatory signals, and malignant transformation [27]. MICA\*009 and \*019 alleles were found strongly associated with BD in a Spanish population [28]. The MICA-A6 allele has been reported to increase the risk of BD in

*Genetics of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.101342*

Japanese and Korean populations. In a recent study, the MICA\*049 allele was found to be significantly higher in BD patients than in controls in a Chinese cohort [29]. On the other hand, Eyerci et al. reported the MICA\*006 (MICA-A6) and MICA\*009 alleles were associated with BD susceptibility in the HLA-B\*51 positive Turkish population. [30]. MICA-A5.1 was indicated a negative correlation with ocular lesions and iridocyclitis in BD patients [31].
