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

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder caused by neutralizing anti-ADAMTS13 autoantibodies. In white individuals, HLA allele DRB1*11 is a predisposing factor for iTTP, whereas DRB1*04 is a protective factor. However, the role of HLA in Asians is unclear. In this study, we analyzed 10 HLA loci using next-generation sequencing in 52 Japanese patients with iTTP, and the allele frequency in the iTTP group was compared with 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 [Pc] = .005), DRB3/4/5*blank (OR, 2.3; Pc = .007), DQA1*01:03 (OR, 2.25; Pc = .006), and DQB1*06:01 (OR,: 2.41; Pc = .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 < .001). DRB1*15:01 and DRB5*01:01 were weak protective factors for iTTP (OR, 0.23; Pc = .076; and OR, 0.23, Pc = .034, respectively). On the other hand, DRB1*11 and DRB1*04 were not associated with iTTP in the Japanese. These findings indicated that predisposing and protective factors for iTTP differ between Japanese and white individuals. HLA-DR molecules encoded by DRB1*08:03 and DRB1*11:01 have different peptide-binding motifs, but interestingly, bound to the shared ADAMTS13 peptide in an in silico prediction model.

• Authors: Kazuya Sakai, Masataka Kuwana, Hidenori Tanaka, Kazuyoshi Hosomichi, Atsushi Hasegawa, Hiroki Uyama, Kenji Nishio, Takashi Omae, Masakatsu Hishizawa, Masashi Matsui, Koji Iwato, Akinao Okamoto, Kazuki Okuhiro, Yukiko Yamashita, Masataka Itoh, Hanae Kumekawa, Naoki Takezako, Noriaki Kawano, Toshihiro Matsukawa, Haruna Sano, Kazuiku Ohshiro, Kunio Hayashi, Yasunori Ueda, Toshiki Mushino, Yoshiyuki Ogawa, Yuji Yamada, Mitsuru Murata, Masanori Matsumoto
• Journal: Blood (Blood) Vol. 135 Issue 26 Pg. 2413-2419 (06 25 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 32253422 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• HLA-DR Antigens
• Peptide Fragments
• ADAMTS13 Protein
• ADAMTS13 protein, human

Topics

• ADAMTS13 Protein (physiology)
• Alleles
• Amino Acid Motifs
• Amino Acid Sequence
• Asian People (genetics)
• Computer Simulation
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• HLA-DR Antigens (genetics, immunology, metabolism)
• Haplotypes
• High-Throughput Nucleotide Sequencing
• Histocompatibility Testing
• Humans
• Japan (epidemiology)
• Male
• Models, Molecular
• Peptide Fragments (metabolism)
• Protein Conformation
• Protein Interaction Mapping
• Purpura, Thrombotic Thrombocytopenic (ethnology, genetics, immunology)