HLA loci predisposing to immune TTP in Japanese: potential role of the shared ADAMTS13 peptide bound to different HLA-DR.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder caused by neutralizing anti-ADAMTS13 autoantibodies. In Caucasians, human leukocyte antigen (HLA) allele DRB1*11 was a predisposing factor for iTTP, while DRB1*04 was a protective factor. However, the role of HLA in Asians is unclear. In this study, we analyzed 10 HLA loci using next-generation sequencing (NGS) in 52 Japanese patients with iTTP, and the allele frequency in the iTTP group was compared to that in a Japanese control group. We identified the following HLA alleles as predisposing factors for iTTP in the Japanese population: DRB1*08:03 (odds ratio [OR]: 3.06, corrected P-values [Pc]=0.005), DRB3/4/5*blank (OR: 2.3, Pc=0.007), DQA1*01:03 (OR: 2.25, Pc=0.006), and DQB1*06:01 (OR: 2.41, Pc=0.003). The estimated haplotype consisting of these 4 alleles was significantly more frequent in the iTTP group than in the control group (30.8% vs. 6.0%, Pc<0.001). DRB1*15:01 and DRB5*01:01 were weak protective factors for iTTP (OR 0.23, Pc=0.076; and OR 0.23, Pc=0.034, respectively). On the other hand, DRB1*11 and DRB1*04 were not associated with iTTP in Japanese. These findings indicated that predisposing and protective factors for iTTP differ between Japanese and Caucasians. HLA-DR molecules encoded by DRB1*08:03 and DRB1*11:01 have different peptide-binding motifs, but interestingly, were capable of binding to the shared ADAMTS13 peptide in an in silico prediction model.