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

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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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De Jong, V. M., Zaldumbide, A., Van Der Slik, A. R., Laban, S., Koeleman, B. P. C., & Roep, B. O. (2016). Variation in the CTLA4 3′UTR has phenotypic consequences for autoreactive T cells and associates with genetic risk for type 1 diabetes. Genes and Immunity, 17(1), 75–78. https://doi.org/10.1038/gene.2015.51

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