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rs10924104 in the expression enhancer motif of CD58 confers susceptibility to human autoimmune diseases

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Abstract

CD58 plays roles in cell adhesion and co-stimulation with antigen presentation from major histocompatibility complex class II on antigen-presenting cells to T-cell antigen receptors on naïve T cells. CD58 reportedly contributes to the development of various human autoimmune diseases. Recently, genome-wide association studies (GWASs) identified CD58 as a susceptibility locus for autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and primary biliary cholangitis (PBC). However, the primary functional variant and molecular mechanisms of susceptibility to autoimmune diseases in the CD58 locus were not clarified. Here, rs10924104, located in the ZNF35-binding motif within the gene expression regulatory motif, was identified as the primary functional variant for SLE, MS, and PBC among genetic variants showing stronger linkage disequilibrium (LD) with GWAS-lead variants in the CD58 locus. Expression-quantitative trait locus (e-QTL) data for each distinct blood cell type and in vitro functional analysis using the CRISPR/Cas9 system corroborated the functional role of rs10924104 in the upregulation of CD58 transcription by the disease-risk allele. Additionally, the strength of disease susceptibility observed in the CD58 locus could be accounted for by the strength of LD between rs10924104 and each GWAS-lead variant. In conclusion, the present study demonstrated for the first time the existence of a shared autoimmune disease-related primary functional variant (i.e., rs10924104) that regulates the expression of CD58. Clarifying the molecular mechanism of disease susceptibility derived from such a shared genetic background is important for understanding human autoimmune diseases and human immunology.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank all patients and volunteers who enrolled in the study. We also thank Dr. Noriko Miyake for the valuable suggestions. We also thank Ms. Yoshimi Shigemori, Ms. Ayumi Nakayama, Ms. Mayumi Ishii, Ms. Takayo Tsuchiura, Ms. Tomoko Suzuki, Ms. Nozomi Komatsuzaki, Ms. Hikari Tokunaga, Ms. Yuko Maeda, Ms. Mizuki Kobayashi (National Center for Global Health and Medicine), Ms. Hitomi Nakamura, and Ms. Yumi Ogami (Nagasaki Medical Center) for technical and administrative assistance.

Funding

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to Yuki Hitomi (22K08065, 19K08413), Yoshihiro Aiba (20K08370), and Minoru Nakamura (17H04169); the NCGM Intramural Research Fund to Yuki Hitomi (23A1007); Clinical Research from the NHO to Minoru Nakamura; Research Program for Rare/Intractable Diseases provided by the Ministry of Health, Labour, and Welfare of Japan to Minoru Nakamura; Platform Program for Promotion of Genome Medicine (19km0405205h9904) from the Japan Agency for Medical Research and Development to Katsushi Tokunaga and Masao Nagasaki; and Takeda Foundation to Yuki Hitomi.

Author information

Authors and Affiliations

  1. Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan

    Yuki Hitomi, Sanami Takada & Chisato Iwabuchi

  2. Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan

    Kazuko Ueno, Yosuke Kawai, Seik-Soon Khor & Katsushi Tokunaga

  3. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan

    Yoshihiro Aiba & Minoru Nakamura

  4. Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Nao Nishida

  5. Database Center for Life Science, Research Organization of Information and Systems, Kashiwa, Japan

    Minae Kawashima

  6. Division of Biomedical Information Analysis, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Masao Nagasaki

  7. Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan

    Minoru Nakamura

  8. Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan

    Minoru Nakamura

  9. Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore

    Seik-Soon Khor

Authors
  1. Yuki Hitomi
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  2. Kazuko Ueno
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  3. Yoshihiro Aiba
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  4. Nao Nishida
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  5. Yosuke Kawai
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  6. Minae Kawashima
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  7. Seik-Soon Khor
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  8. Sanami Takada
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  9. Chisato Iwabuchi
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  10. Masao Nagasaki
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  11. Katsushi Tokunaga
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  12. Minoru Nakamura
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Contributions

Study concept and design: YH, M. Nagasaki, TK, M. Nakamura; Acquisition of data: YH, KU, ST, CI, M. Nagasaki; Analysis and interpretation of data: YH, YA, KU, NN, YK, MK, SK, ST, CI, M. Nagasaki, M. Nakamura; Drafting of the manuscript: YH, M. Nakamura; Obtained funding: YH, YA, M. Nagasaki, KT, M. Nakamura; Study supervision: M. Nagasaki, KT, M. Nakamura. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yuki Hitomi.

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Conflict of interest

The authors declare no competing financial interests.

Ethics approval

The study was approved by the Committee on Research Ethics of the National Center for Global Health and Medicine, and the National Hospital Organization. All methods were performed in accordance with the ethical guidelines and regulations.

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Hitomi, Y., Ueno, K., Aiba, Y. et al. rs10924104 in the expression enhancer motif of CD58 confers susceptibility to human autoimmune diseases. Hum. Genet. 143, 19–33 (2024). https://doi.org/10.1007/s00439-023-02617-2

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  • DOI: https://doi.org/10.1007/s00439-023-02617-2

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