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.
OBJECTIVE
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.


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
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.
Howson
J M M
JM
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, CB2 0XY, UK.
Dunger
D B
DB
Nutland
S
S
Stevens
H
H
Wicker
L S
LS
Todd
J A
JA
D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics*; D000943:Antigens, Differentiation / Q000235:genetics*; D001324:Autoantigens / Q000737:chemistry; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007453:Iodide Peroxidase / Q000737:chemistry; D033862:Iron-Binding Proteins / Q000737:chemistry; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D012737:Sex Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D033862:Iron-Binding Proteins; C056658:TPO protein, human; D007453:Iodide Peroxidase; C516765:PTPN22 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases