Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases

Mineto Ota¹, Yasuo Nagafuchi², Hiroaki Hatano³, Kazuyoshi Ishigaki⁴, Chikashi Terao⁵, Yusuke Takeshima², Haruyuki Yanaoka³, Satomi Kobayashi³, Mai Okubo³, Harumi Shirai³, Yusuke Sugimori³, Junko Maeda³, Masahiro Nakano³, Saeko Yamada³, Ryochi Yoshida³, Haruka Tsuchiya³, Yumi Tsuchida³, Shuji Akizuki⁶, Hajime Yoshifuji⁶, Koichiro Ohmura⁶, Tsuneyo Mimori⁶, Ken Yoshida⁷, Daitaro Kurosaka⁷, Masato Okada⁸, Keigo Setoguchi⁹, Hiroshi Kaneko¹⁰, Nobuhiro Ban¹¹, Nami Yabuki¹¹, Kosuke Matsuki¹¹, Hironori Mutoh¹¹, Sohei Oyama¹¹, Makoto Okazaki¹¹, Hiroyuki Tsunoda¹¹, Yukiko Iwasaki³, Shuji Sumitomo³, Hirofumi Shoda³, Yuta Kochi¹², Yukinori Okada¹³, Kazuhiko Yamamoto¹⁴, Tomohisa Okamura¹⁵, Keishi Fujio¹⁶

Affiliations

¹ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: otam-int@h.u-tokyo.ac.jp.
² Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
³ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁴ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
⁶ Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
⁷ Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
⁸ Immuno-Rheumatology Center, St. Luke's International Hospital, Tokyo 104-8560, Japan.
⁹ Division of Collagen Disease, Department of Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo 113-0021, Japan.
¹⁰ Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
¹¹ Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
¹² Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
¹³ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
¹⁴ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
¹⁵ Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
¹⁶ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: fujiok-int@h.u-tokyo.ac.jp.

PMID: 33930287
DOI: 10.1016/j.cell.2021.03.056

Free article

Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases

Mineto Ota et al. Cell. 2021.

Free article

. 2021 May 27;184(11):3006-3021.e17.

doi: 10.1016/j.cell.2021.03.056. Epub 2021 May 1.

Authors

Affiliations

¹ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: otam-int@h.u-tokyo.ac.jp.
² Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
³ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁴ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
⁶ Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
⁷ Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
⁸ Immuno-Rheumatology Center, St. Luke's International Hospital, Tokyo 104-8560, Japan.
⁹ Division of Collagen Disease, Department of Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo 113-0021, Japan.
¹⁰ Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
¹¹ Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
¹² Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
¹³ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
¹⁴ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
¹⁵ Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
¹⁶ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: fujiok-int@h.u-tokyo.ac.jp.

PMID: 33930287
DOI: 10.1016/j.cell.2021.03.056

Abstract

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.

Keywords: Immune Cell Gene Expression Atlas from the University of Tokyo; cell-type-specific eQTL; context-dependent eQTL; expression quantitative trait loci; gene regulation; immune cell; immune-mediated disease; immunogenetics; systemic lupus erythematosus; transcriptome.

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Conflict of interest statement

Declaration of interests N.B., N.Y., K.M, H.M., S.O., M. Okazaki, and H. Tsunoda are employees of Chugai Pharmaceutical. T.O., M. Ota, Y.N., and Y. Takeshima belong to the Social Cooperation Program, Department of Functional Genomics and Immunological Diseases, supported by Chugai Pharmaceutical. K.F. receives consulting honoraria and research support from Chugai Pharmaceutical.

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Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases

Affiliations

Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

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