Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease

Abstract

Behçet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçet's disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçet's disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10(-50)). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10(-26)), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10(-14)) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10(-18)) were also identified and replicated.

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

“…The association of rs116799036 with BD was seven orders of magnitude weaker than that of HLA-B*51 (Table S3). Furthermore, in contrast to a previous report (14), the association of HLA-B*51 with BD remained significant even after conditioning for the effect of rs116799036 (p regressor = 9.2 × 10 −8 ; Table S3). …”

“…Using haplotype analysis of HLA-B*51 and SNPs in the HLA-B/MICA region, we demonstrated the importance of HLA-B*51 itself in BD risk. This observation is contrary to a recent report by Hughes et al (14) that suggested that, instead of HLA-B*51, rs116799036, a noncoding variant between HLA-B and MICA, was the true source of BD risk in this region. In our study, HLA-B*51 was much more strongly associated with BD than was any SNP, including rs116799036 (Fig.…”

“…To examine the role of rs116799036, a noncoding SNP recently proposed to underlie the effect of HLA-B*51 on BD risk (14), we directly genotyped this marker in our collection. The association of rs116799036 with BD was seven orders of magnitude weaker than that of HLA-B*51 (Table S3).…”

“…It also has been argued that variants in or around MHC class I polypeptide-related sequence A (MICA), the centromeric neighbor of HLA-B that encodes the MHC-I chain-related sequence A, contribute to BD susceptibility (11). However, efforts to parse the effects of MICA and HLA-B alleles definitively have been confounded by their particularly strong LD (11)(12)(13)(14). Additionally, HLA-A has been identified as a BD susceptibility locus in numerous studies (2,3,(14)(15)(16)(17), and it has been suggested that HLA-C contributes to BD risk, as well (14).…”

HLA-B*51 the primary risk in Behçet disease

“…Recently genome-wide association studies (GWASs) in different patient populations showed specific genes linked to BD in different ethnic groups; however, all the studies identified the HLA-B loci as the strongest association (9)(10)(11). However, in a recent study, deep sequencing of the HLA region identified an SNP, rs116799036, close to MICA that gave the strongest association and was independent of HLA-B*51 (12). By comparison with Ombrello et al, rs116799036 had a much weaker association with BD than HLA-B*51, which remained significant after the data were conditioned for this SNP.…”