Along with human leukocyte antigen gene encoding B*51 (HLA-B*51) and areas including the major histocompatibility complex class I, genome-wide association studies have recognized numerous other BD susceptibility genes including those encoding interleukin (IL)-10, IL-12 receptor β 2 (IL-12RB2), IL-23 receptor (IL-23R), C-C chemokine receptor 1 gene, signal transducer and activator of transcription 4 (STAT4), endoplasmic reticulum aminopeptidase (ERAP1), and genes encoding killer cell lectin-like receptor family members (KLRC4-KLRK1).
The distinct effects of both enzymes on the HLA-B*51 peptidome provide a basis for their differential association with Behçet's disease and suggest a pathogenetic role of the B*51:01 peptidome.
To our knowledge, this is the first analysis of KIR3DL1/S1 allelic variation in Behçet disease and may provide insight into the pathogenic role of <i>HLA-B*51</i> and its interaction with KIR3DL1/S1.
In conclusion, two peptides that had high affinity to HLA-B*51:01 in computerized binding prediction showed significantly higher response in HLA-B*51:01-positive patients with BD, indicating the usefulness of computerized simulations for identifying autoreactive peptides to HLAs.
Our findings suggest that gene-gene interactions between HLA-B*51 and ERAP1 variants is important for BD development, however, ERAP1 variants which interact with HLA-B*51 may differ among disease phenotypes or populations.
Among these variants, the genetic variant associated with Behçet's disease in the <i>HLA-B</i>/<i>MICA</i> region, which tags <i>HLA-B*51</i>, is within novel long intergenic noncoding RNA transcripts that are exclusively expressed from the haplotype with the protective but not the disease risk allele.
HLA-C1<sup>Asn80</sup> showed a protective effect against BD, whereas HLA-C2<sup>Lys80</sup>, HLA-B-Bw4<sup>Ile80</sup>, HLA-B5, and HLA-B51 were associated with a susceptibility risk for BD.
HLA-A*29 and HLA-B*51 are associated with birdshot uveitis and Behçet's disease, respectively, and are used as a diagnostic criterion in patients with suspected disease, requiring their detection in diagnostic laboratories.
However, the low prevalence of HLA-B*51 in many patients with bone fide disease, especially in non-endemic regions, suggests other factors must also be operative in Behçet syndrome.
The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD.
Neither the BD-associated genetic risk locus within the HLA-B/MICA region nor being on immunosuppressive medications explained the differences between patients and controls.
The Behçet's disease (BD)-associated human leukocyte antigen (HLA) allele, HLA-B*51 (B*51), encodes a ligand for a pair of allelic killer immunoglobulin-like receptors (KIR) present on cytotoxic cells-KIR3DL1, which inhibits their cytotoxicity, and KIR3DS1, which activates their cytotoxic activity.
Genetic studies have supported the strong association of human leukocyte antigen-B and Behçet's disease, and high production of tumour necrosis factor and low production of interleukin (IL)-10, which have led to therapy based on controlling these effects.
Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behçet's disease risk by altering the peptides available for binding to HLA-B*51.
Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B.
We found that the HLA-B*51 allele and the rs76546355/rs116799036 MHC SNP are independent genetic risk factors for BD in Iranian, and that positivity for the rs76546355/rs116799036 risk allele, but not for B*51, does correlate with specific demographic characteristics or clinical manifestations in BD patients.