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Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Author

Listed:
  • Hironori Ueda

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Joanna M. M. Howson

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Laura Esposito

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Joanne Heward

    (University of Birmingham)

  • Snook

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Giselle Chamberlain

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Daniel B. Rainbow

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Kara M. D. Hunter

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Annabel N. Smith

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Gianfranco Di Genova

    (University of Cambridge, Wellcome Trust/MRC Building
    Southampton General Hospital)

  • Mathias H. Herr

    (University of Cambridge, Wellcome Trust/MRC Building
    Otto-Heubner-Centrum, Charité, Humboldt-University of Berlin)

  • Ingrid Dahlman

    (University of Cambridge, Wellcome Trust/MRC Building
    Huddinge University Hospital)

  • Felicity Payne

    (Universita di Cagliari)

  • Deborah Smyth

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Christopher Lowe

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Rebecca C. J. Twells

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Sarah Howlett

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Barry Healy

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Sarah Nutland

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Helen E. Rance

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Vin Everett

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Luc J. Smink

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Alex C. Lam

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Heather J. Cordell

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Neil M. Walker

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Cristina Bordin

    (University of Cambridge, Wellcome Trust/MRC Building
    Hutchison/MRC Research Centre)

  • John Hulme

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Costantino Motzo

    (Universita di Cagliari)

  • Francesco Cucca

    (Universita di Cagliari)

  • J. Fred Hess

    (Merck Research Laboratories)

  • Michael L. Metzker

    (Merck Research Laboratories
    Baylor College of Medicine)

  • Jane Rogers

    (Wellcome Trust Sanger Institute)

  • Simon Gregory

    (University of Helsinki)

  • Amit Allahabadia

    (University of Birmingham
    University of Sheffield, Northern General Hospital)

  • Ratnasingam Nithiyananthan

    (University of Birmingham)

  • Eva Tuomilehto-Wolf

    (University of Helsinki)

  • Jaakko Tuomilehto

    (University of Helsinki
    University of Helsinki)

  • Polly Bingley

    (University of Bristol)

  • Kathleen M. Gillespie

    (University of Bristol)

  • Dag E. Undlien

    (Rikshospitalet University Hospital and Institute of Medical Genetics, Ulleval University Hospital, University of Oslo
    University of Oslo)

  • Kjersti S. Rønningen

    (Norwegian Institute of Public Health)

  • Cristian Guja

    (Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases ‘N. Paulescu’)

  • Constantin Ionescu-Tîrgovişte

    (Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases ‘N. Paulescu’)

  • David A. Savage

    (Queen's University Belfast, Belfast City Hospital)

  • A. Peter Maxwell

    (Belfast City Hospital)

  • Dennis J. Carson

    (Queen's University Belfast)

  • Chris C. Patterson

    (Queen's University Belfast)

  • Jayne A. Franklyn

    (University of Birmingham)

  • David G. Clayton

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Laurence B. Peterson

    (Merck Research Laboratories)

  • Linda S. Wicker

    (University of Cambridge, Wellcome Trust/MRC Building)

  • John A. Todd

    (University of Cambridge, Wellcome Trust/MRC Building)

  • Stephen C. L. Gough

    (University of Birmingham)

Abstract

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)—which encodes a vital negative regulatory molecule of the immune system—as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1?kb 3′ region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

Suggested Citation

  • Hironori Ueda & Joanna M. M. Howson & Laura Esposito & Joanne Heward & Snook & Giselle Chamberlain & Daniel B. Rainbow & Kara M. D. Hunter & Annabel N. Smith & Gianfranco Di Genova & Mathias H. Herr &, 2003. "Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease," Nature, Nature, vol. 423(6939), pages 506-511, May.
    • Handle: RePEc:nat:nature:v:423:y:2003:i:6939:d:10.1038_nature01621
    DOI: 10.1038/nature01621
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    Cited by:

    1. Kensuke Yamaguchi & Kazuyoshi Ishigaki & Akari Suzuki & Yumi Tsuchida & Haruka Tsuchiya & Shuji Sumitomo & Yasuo Nagafuchi & Fuyuki Miya & Tatsuhiko Tsunoda & Hirofumi Shoda & Keishi Fujio & Kazuhiko , 2022. "Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Kaitlyn A. Lagattuta & Hannah L. Park & Laurie Rumker & Kazuyoshi Ishigaki & Aparna Nathan & Soumya Raychaudhuri, 2024. "The genetic basis of autoimmunity seen through the lens of T cell functional traits," Nature Communications, Nature, vol. 15(1), pages 1-6, December.
    3. Clemens Hinterleitner & Jasmin Strähle & Elke Malenke & Martina Hinterleitner & Melanie Henning & Marco Seehawer & Tatjana Bilich & Jonas Heitmann & Martina Lutz & Sven Mattern & Sophia Scheuermann & , 2021. "Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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