Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis

Yukinori Okada, Akari Suzuki, Katsunori Ikari, Chikashi Terao, Yuta Kochi, Koichiro Ohmura, Koichiro Higasa, Masato Akiyama, Kyota Ashikawa, Masahiro Kanai, Jun Hirata, Naomasa Suita, Yik Ying Teo, Huji Xu, Sang Cheol Bae, Atsushi Takahashi, Yukihide Momozawa, Koichi Matsuda, Shigeki Momohara, Atsuo TaniguchiRyo Yamada, Tsuneyo Mimori, Michiaki Kubo, Matthew A. Brown, Soumya Raychaudhuri, Fumihiko Matsuda, Hisashi Yamanaka, Yoichiro Kamatani, Kazuhiko Yamamoto

研究成果: Contribution to journalArticle

31 引用 (Scopus)

抜粋

Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10−9), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.

元の言語英語
ページ(範囲)366-374
ページ数9
ジャーナルAmerican journal of human genetics
99
発行部数2
DOI
出版物ステータス出版済み - 8 4 2016

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

フィンガープリント Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

  • これを引用

    Okada, Y., Suzuki, A., Ikari, K., Terao, C., Kochi, Y., Ohmura, K., Higasa, K., Akiyama, M., Ashikawa, K., Kanai, M., Hirata, J., Suita, N., Teo, Y. Y., Xu, H., Bae, S. C., Takahashi, A., Momozawa, Y., Matsuda, K., Momohara, S., ... Yamamoto, K. (2016). Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis. American journal of human genetics, 99(2), 366-374. https://doi.org/10.1016/j.ajhg.2016.06.019