TY - JOUR
T1 - HLA loci predisposing to immune TTP in Japanese
T2 - Potential role of the shared ADAMTS13 peptide bound to different HLA-DR
AU - Sakai, Kazuya
AU - Kuwana, Masataka
AU - Tanaka, Hidenori
AU - Hosomichi, Kazuyoshi
AU - Hasegawa, Atsushi
AU - Uyama, Hiroki
AU - Nishio, Kenji
AU - Omae, Takashi
AU - Hishizawa, Masakatsu
AU - Matsui, Masashi
AU - Iwato, Koji
AU - Okamoto, Akinao
AU - Okuhiro, Kazuki
AU - Yamashita, Yukiko
AU - Itoh, Masataka
AU - Kumekawa, Hanae
AU - Takezako, Naoki
AU - Kawano, Noriaki
AU - Matsukawa, Toshihiro
AU - Sano, Haruna
AU - Ohshiro, Kazuiku
AU - Hayashi, Kunio
AU - Ueda, Yasunori
AU - Mushino, Toshiki
AU - Ogawa, Yoshiyuki
AU - Yamada, Yuji
AU - Murata, Mitsuru
AU - Matsumoto, Masanori
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/6/25
Y1 - 2020/6/25
N2 - 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] 5.005), DRB3/4/5*blank (OR, 2.3; Pc 5.007), DQA1*01:03 (OR, 2.25; Pc 5.006), and DQB1*06:01 (OR,: 2.41; Pc 5.003). 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 5.076; and OR, 0.23, Pc 5.034, 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.
AB - 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] 5.005), DRB3/4/5*blank (OR, 2.3; Pc 5.007), DQA1*01:03 (OR, 2.25; Pc 5.006), and DQB1*06:01 (OR,: 2.41; Pc 5.003). 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 5.076; and OR, 0.23, Pc 5.034, 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.
UR - https://www.scopus.com/pages/publications/85087097843
UR - https://www.scopus.com/pages/publications/85087097843#tab=citedBy
U2 - 10.1182/blood.2020005395
DO - 10.1182/blood.2020005395
M3 - Article
C2 - 32253422
AN - SCOPUS:85087097843
SN - 0006-4971
VL - 135
SP - 2413
EP - 2419
JO - Blood
JF - Blood
IS - 26
ER -