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

Diabetologia. 2007 Apr;50(4):741-6. doi: 10.1007/s00125-007-0603-6. Epub 2007 Feb 14.

Abstract

Aims/hypothesis: 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.

Materials and methods: 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.

Results: 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 = 1.86 x 10(-15)). TPOAbs status did not correlate with age at diagnosis of type 1 diabetes or with PTPN22 (Arg620Trp; rs2476601).

Conclusions/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Alleles
  • Antigens, CD / genetics*
  • Antigens, Differentiation / genetics*
  • Autoantigens / chemistry
  • Autoimmunity
  • CTLA-4 Antigen
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / diagnosis*
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / therapy*
  • Female
  • Genetic Variation
  • Humans
  • Infant
  • Infant, Newborn
  • Iodide Peroxidase / chemistry
  • Iron-Binding Proteins / chemistry
  • Male
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Protein Tyrosine Phosphatases / genetics
  • Sex Factors

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Autoantigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Iron-Binding Proteins
  • TPO protein, human
  • Iodide Peroxidase
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Protein Tyrosine Phosphatases