In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association.
Genetic variants of ERAP1 (leading to distinct allotypes) are linked with specific autoinflammatory disorders, such as ankylosing spondylitis and Behçet's disease.
Specific HLA antigens were also found in other forms of uveitis such as Reiter's disease (HLA-B 27), Behcet's syndrome (HLA-B 5), VKH syndrome (HLA-Bw 22J) and ocular histoplasmosis (HLA-B 7).
Our findings not only confirmed the association of IL10/rs1800871 and IL23R-IL12RB2/rs924080 with BD but also identified 2 susceptibility single nucleotide polymorphisms in IL10 and IL23R-IL12RB2 (rs3024490 and rs12141431) with BD in Han Chinese.
Behçet's disease (BD) susceptibility had been associated with single-nucleotide polymorphisms (SNPs) in IL23R-IL12RB2, IL10, STAT4, or ERAP1 locus in Japanese, Turkish, Chinese, and other populations, but not in a Korean genome-wide association study (GWAS).
Of particular note, the results of this study suggest that the presence of HLA-B 51 and the absence of HLA-B35 can be regarded as laboratory risk factors of venous thrombosis in patients with Behçet's disease.
Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51(-) German cohort of BD patients [p(c) = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31].
However, recent genome-wide association studies have confirmed that HLA-B*51 is primarily associated with BD and that there are multiple susceptibility loci other than HLA-B*51.
Non-HLA genetic associations such as endoplasmic reticulum aminopeptidase 1 (ERAP1), interleukin 23 receptor (IL23R) and IL10 variations suggest that BD shares susceptibility genes and inflammatory pathways with spondyloarthritis.
Our study indicates that functional TNF-α, IL10 genotypes or combined TNF-α, IL10 genotypes do not play a role in BS susceptibility in Turkish BS patients.
There is no evidence supporting the use of HLA-B*51 as a diagnostic or prognostic marker for BD, and more clinical data must be collected in addition to basic immunological studies to exploit the potential of HLA-B*51 as a biomarker for BD management.
Regarding the non-HLA genes, the three SNPs located in IL23R and one of the SNPs in IL10 were found to be significantly associated with susceptibility to BD in our population.
Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population.
However, they are associated with two different vasculitides (HLA-B*51 in Behçet's disease and HLA-B*52 in Takayasu's arteritis (TAK)) and with major clinical and immunological differences.