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

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.