title: Genetics of Autoimmune Thyroiditis in Type 1 Diabetes Reveals a Novel Association With DPB1*0201: Data From the Type 1 Diabetes Genetics Consortium.
abstract: BACKGROUND
  Autoimmune thyroiditis occurs in 10-25% of patients with type 1 diabetes (T1D). Most of these patients are also positive for thyroid peroxidase (TPO) antibodies. Thyroid dysfunction complicates T1D metabolic control and is a component of the autoimmune polyglandular syndrome (APS, type 2 or 3). Previous studies of isolated T1D and of T1D combined with other autoimmune disorders showed genetic susceptibility for alleles in HLA-DQB1 and -DRB1 and also CTLA4 and PTPN22.
  
  
  METHODS
  We analyzed the Type 1 Diabetes Genetics Consortium Autoantibody Workshop data by differentiating those T1D probands with and without TPO antibodies or thyroid disease with respect to polymorphisms in HLA, CTLA4, INS, PTPN22, and VDR, taking into account the ethnic origin. Genotype and clinical/immunogenic phenotype data were analyzed by gene counting methods and logistic regression analysis.
  
  
  RESULTS
  The presence of TPO antibodies (25.2%) and thyroid disease (8.4%) was associated with older age, female sex, and presence of other autoantibodies (GAD65, ATPase, 21-OH) (all P<0.001). The highest prevalence was in patients of Hispanic ancestry (31%) and the lowest in those of African ancestry (8%). In T1D non-Hispanic whites, HLA-DRB1*0101 is significantly (P<0.0001) less frequent in TPO-positive than in TPO-negative individuals, whereas HLA-DRB1*0404, -DQB1*0301, and -DPB1*0201 are significantly (P<0.0001) more frequent. Subjects with a high titer of TPO autoantibodies and with thyroid disease were associated with female sex and older age and negatively associated with DRB1*0401-DQB1*0302 (P<0.0001). No significant differences were observed for an association of TPO positivity or thyroid disease with single nucleotide polymorphisms in the INS, CTLA4, or VDR loci, with nominal significance (P=0.01) for PTPN22 R620W variant.
  
  
  CONCLUSIONS
  Thyroid autoimmunity is highly prevalent in T1D patients of non-Hispanic white, Asian, or Hispanic origin. The strongest disease risk is conferred by female sex and older age. This risk is modulated by HLA-DRB1 and HLA-DPB1 loci. The immunogenetic profile for T1D with thyroid autoimmunity may identify distinct pathways regulating polyglandular autoimmunity and disease.
authors.affiliation: University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kahles
authors.affiliation: Barbara Davis Center for Childhood Diabetes, Aurora, CO.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.affiliation: Barbara Davis Center for Childhood Diabetes, Aurora, CO.
authors.forename: Peter
authors.initials: P
authors.lastname: Baker
authors.affiliation: Barbara Davis Center for Childhood Diabetes, Aurora, CO.
authors.forename: George
authors.initials: G
authors.lastname: Eisenbarth
authors.affiliation: University Hospital Frankfurt, Frankfurt am Main, Germany badenhoop@em.uni-frankfurt.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Badenhoop
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics / Q000276:immunology; D033862:Iron-Binding Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000097:blood / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D059868:HLA-DP beta-Chains; C500433:HLA-DPB1*02:01 antigen; D059811:HLA-DRB1 Chains; D033862:Iron-Binding Proteins; C056658:TPO protein, human; D007453:Iodide Peroxidase; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22