A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

HLA haplotypes DRB1*03_DQB1*02 and DRB1*04_DQB1*0302, and allelic variation of the T cell regulatory gene cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and of the T cell activation gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22) have been associated with type 1 diabetes and autoimmune thyroid disease. Using thyroid peroxidase autoantibodies (TPOAbs) as an indicator of thyroid autoimmunity, we assessed whether the association of these loci is different in type 1 diabetes patients with TPOAbs than in those without. TPOAbs were measured in 4,364 type 1 diabetic patients from across Great Britain, 67% of whom were aged under 18 years. These patients and 6,866 geographically matched control subjects were genotyped at CTLA4, PTPN22, HLA-DRB1 and HLA-DQB1. TPOAbs were detected in 462 (10.6%) of the type 1 diabetic patients. These patients had a stronger association with CTLA4 (odds ratio [OR]=1.49 for the G allele of the single nucleotide polymorphism rs3087243; 95% CI=1.29-1.72) than did the TPOAbs-negative patients (p=0.0004; OR=1.16; 95% CI=1.10-1.24) or type 1 diabetes patients overall (OR=1.20; 95% CI=1.13-1.27). The ratio of women:men was higher (1.94:1) in this subgroup than in type 1 diabetes patients without TPOAbs (0.94:1; p=1.86x10(-15)). TPOAbs status did not correlate with age at diagnosis of type 1 diabetes or with PTPN22 (Arg620Trp; rs2476601). Our results identify a subgroup of type 1 diabetic patients that is sensitive to allelic variation of the negative regulatory molecule CTLA-4 and indicate that TPOAbs testing could be used to subclassify type 1 diabetes patients for inclusion in genetic, biological or clinical studies.