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Variation in the CTLA4 3′UTR has phenotypic consequences for autoreactive T cells and associates with genetic risk for type 1 diabetes

Genes & Immunity volume 17, pages 75–78 (2016)Cite this article

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Abstract

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a protein receptor that downregulates the immune system. CTLA4 gene variants associate with various autoimmune diseases, including type 1 diabetes. Fine mapping of the genetic risk has shown that the genomic region near CTLA4 marked by the single-nucleotide polymorphism (SNP) CT60A/G (rs3087243) acts as a susceptibility factor. Yet, the functional basis for the increased susceptibility conferred by rs3087243 remains unclear. We demonstrate that the length of the dinucleotide (AT)n repeat within the CTLA4 3’ untranslated region (3′UTR) strongly associates with the risk of SNP CT60A/G (P<6.5 × 10−72). Genomic (AT)n repeat length inversely correlated with CTLA4 messenger RNA (mRNA) and protein levels in islet autoreactive T-cell lines. Transfer of a long (AT)n element into T cells lead to a reduction of mRNA compared to a short (AT)n element. Thus, this study provides evidence for a role of the CTLA4 3′UTR (AT)n repeat in the increased genetic risk for islet autoimmunity associated with the CTLA4 locus.

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Acknowledgements

This work was funded by grants from the Dutch Diabetes Research Foundation, the ZonMW VICI program, The Juvenile Diabetes Research Foundation, The Leiden University Medical Center and the 7th Framework Program of the European Commission.

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Authors and Affiliations

  1. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    V M de Jong, A R van der Slik, S Laban & B O Roep

  2. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

    A Zaldumbide

  3. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    B P C Koeleman

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  1. V M de Jong
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  2. A Zaldumbide
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Correspondence to B O Roep.

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de Jong, V., Zaldumbide, A., van der Slik, A. et al. Variation in the CTLA4 3′UTR has phenotypic consequences for autoreactive T cells and associates with genetic risk for type 1 diabetes. Genes Immun 17, 75–78 (2016). https://doi.org/10.1038/gene.2015.51

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