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 Taniguchi & 9 others Ryo Yamada, Tsuneyo Mimori, Michiaki Kubo, Matthew A. Brown, Soumya Raychaudhuri, Fumihiko Matsuda, Hisashi Yamanaka, Yoichiro Kamatani, Kazuhiko Yamamoto

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)366-374
Number of pages9
JournalAmerican Journal of Human Genetics
Volume99
Issue number2
DOIs
Publication statusPublished - 04-08-2016

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HLA Antigens
Rheumatoid Arthritis
Genes
Major Histocompatibility Complex
Population
Validation Studies
Quantitative Trait Loci
Linkage Disequilibrium
Genetic Predisposition to Disease
Allergy and Immunology
Autoantibodies

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Okada, Y., Suzuki, A., Ikari, K., Terao, C., Kochi, Y., Ohmura, K., ... 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
Okada, Yukinori ; Suzuki, Akari ; Ikari, Katsunori ; Terao, Chikashi ; Kochi, Yuta ; Ohmura, Koichiro ; Higasa, Koichiro ; Akiyama, Masato ; Ashikawa, Kyota ; Kanai, Masahiro ; Hirata, Jun ; Suita, Naomasa ; Teo, Yik Ying ; Xu, Huji ; Bae, Sang Cheol ; Takahashi, Atsushi ; Momozawa, Yukihide ; Matsuda, Koichi ; Momohara, Shigeki ; Taniguchi, Atsuo ; Yamada, Ryo ; Mimori, Tsuneyo ; Kubo, Michiaki ; Brown, Matthew A. ; Raychaudhuri, Soumya ; Matsuda, Fumihiko ; Yamanaka, Hisashi ; Kamatani, Yoichiro ; Yamamoto, Kazuhiko. / Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 2. pp. 366-374.
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abstract = "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.",
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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, YY, Xu, H, Bae, SC, Takahashi, A, Momozawa, Y, Matsuda, K, Momohara, S, Taniguchi, A, Yamada, R, Mimori, T, Kubo, M, Brown, MA, Raychaudhuri, S, Matsuda, F, Yamanaka, H, Kamatani, Y & Yamamoto, K 2016, 'Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis', American Journal of Human Genetics, vol. 99, no. 2, pp. 366-374. https://doi.org/10.1016/j.ajhg.2016.06.019

Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis. / Okada, Yukinori; Suzuki, Akari; Ikari, Katsunori; Terao, Chikashi; Kochi, Yuta; Ohmura, Koichiro; Higasa, Koichiro; Akiyama, Masato; Ashikawa, Kyota; Kanai, Masahiro; Hirata, Jun; Suita, Naomasa; Teo, Yik Ying; Xu, Huji; Bae, Sang Cheol; Takahashi, Atsushi; Momozawa, Yukihide; Matsuda, Koichi; Momohara, Shigeki; Taniguchi, Atsuo; Yamada, Ryo; Mimori, Tsuneyo; Kubo, Michiaki; Brown, Matthew A.; Raychaudhuri, Soumya; Matsuda, Fumihiko; Yamanaka, Hisashi; Kamatani, Yoichiro; Yamamoto, Kazuhiko.

In: American Journal of Human Genetics, Vol. 99, No. 2, 04.08.2016, p. 366-374.

Research output: Contribution to journalArticle

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T1 - Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis

AU - Okada, Yukinori

AU - Suzuki, Akari

AU - Ikari, Katsunori

AU - Terao, Chikashi

AU - Kochi, Yuta

AU - Ohmura, Koichiro

AU - Higasa, Koichiro

AU - Akiyama, Masato

AU - Ashikawa, Kyota

AU - Kanai, Masahiro

AU - Hirata, Jun

AU - Suita, Naomasa

AU - Teo, Yik Ying

AU - Xu, Huji

AU - Bae, Sang Cheol

AU - Takahashi, Atsushi

AU - Momozawa, Yukihide

AU - Matsuda, Koichi

AU - Momohara, Shigeki

AU - Taniguchi, Atsuo

AU - Yamada, Ryo

AU - Mimori, Tsuneyo

AU - Kubo, Michiaki

AU - Brown, Matthew A.

AU - Raychaudhuri, Soumya

AU - Matsuda, Fumihiko

AU - Yamanaka, Hisashi

AU - Kamatani, Yoichiro

AU - Yamamoto, Kazuhiko

PY - 2016/8/4

Y1 - 2016/8/4

N2 - 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.

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