HLA-B*51 the primary risk in Behçet disease.

Behçet disease (BD) is a multisystem autoinflammatory condition characterized by mucosal ulceration and predominantly neutropilic inflammation of immune privileged sites including the eye, brain, and synovial joint (1). In PNAS, Ombrello et al. analyze a combination of directly ascertained and imputated single nucleotide polymorphisms (SNPs) in the HLA-B region in Turkish patients with BD (2). HLA-B*51 was the largest single risk factor for BD, with smaller, independent effects of HLA-B*15 and HLA-B*27. HLAB*15 was also significantly associated in HLA-B*51 patients. Analysis of 32,869 SNPs across the MHC region identified HLA and MHC class I polypeptide-related sequence A (MICA) as the strongest association. Conditioning on HLA-B*51 and rs79556279, the strongest associated SNPs, 4.5 kb upstream of HLA-B loci showed no other significant SNPs. Moreover HLA-B*51 and rs79556279 are in strong linkage disequilibrium. Two other regions, one tetrameric to HLA-C and the second in a region that includes HLA-A, were associated with BD, but the former was lost on conditioning for rs79556279. Associations with HLA-A, particularly HLA-A26, have been previously reported, particularly in Japanese patients with BD. Finally, using logistical regression and conditioning for HLA-B*51, HLA-A*03 was shown to be significantly protective for BD, and HLA-A*49 was protective in HLAB*51 individuals. To further understand the difference to between susceptible and protective alleles, amino acid motifs were assessed. Amino acids at positions 67, 97, 116, and 152 significantly and independently influenced the risk of developing BD.