title: HLA-DR genotypes influence age at disease onset in children and juveniles with type 1 diabetes mellitus.
abstract: OBJECTIVE
  To investigate HLA-DR genotype in association with chronological age or calendar year of disease onset and the time trend of genotype frequencies from 1969 to 2009. Additionally, to examine genotype frequency in relation to B-cell-, islet cell antibodies (ICA)-, autoantibodies to insulin-, insulinoma antigen 2 (IA2)-, glutamic acid decarboxylase-antibody positivity, thyroid antibody positivity, thyroid diseases or coeliac antibody positivity. Genotype associations with gender and ethnicity are also analyzed.
  
  
  METHODS
  HLA-typed children and juveniles (n=1445) aged <or=20 years at disease onset from the German/Austrian DPV-database were examined. chi(2) statistics and mixed hierarchical logistic regression models were used to compare genotype frequencies and establish associations with age at disease manifestation, autoimmune antibodies/diseases, ethnicity and time trend.
  
  
  RESULTS
  Subjects aged <6 years predominantly carried the genotype HLA-DR3/4 (25.2%), whereas in subjects aged >12 years the most prevalent HLA-DR genotype was X/X (18.1%). IA2 positivity was associated with HLA-DR4/X and HLA-DR3/4 positivity (P=0.011), and hypothyroidism was linked to HLA-DR4/4 (P=0.0103). More females carried the HLA-DR4/4 genotype (18.2 vs 12.7% P=0.0048) or were thyroid antibody positive (24.5 vs 14.7% P=0.0001). Larger numbers of <6 year olds were coeliac antibody positive than >12 year olds (14.8 vs 9.1% P=0.0037). No associations between migration background and B-cell-, thyroid- or coeliac-antibody positivity, and no time trend were found.
  
  
  CONCLUSIONS
  HLA-DR genotype associated with age at disease onset, ICA positivity and hypothyroidism; female gender with thyroid antibody positivity and low age of diabetes onset with coeliac antibody positivity.
authors.affiliation: Department of Epidemiology, Faculty of Medicine, Division of Endocrinology and Diabetes, Clinic for Internal Medicine I, University of Ulm, Ulm 89081, Germany. wendy.awa@uni-ulm.de
authors.forename: W L
authors.initials: WL
authors.lastname: Awa
authors.forename: B O
authors.initials: BO
authors.lastname: Boehm
authors.forename: T
authors.initials: T
authors.lastname: Kapellen
authors.forename: B
authors.initials: B
authors.lastname: Rami
authors.forename: P
authors.initials: P
authors.lastname: Rupprath
authors.forename: W
authors.initials: W
authors.lastname: Marg
authors.forename: M
authors.initials: M
authors.lastname: Becker
authors.forename: R W
authors.initials: RW
authors.lastname: Holl
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001323:Autoantibodies / Q000235:genetics; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen / Q000235:genetics; D015804:HLA-DR4 Antigen / Q000235:genetics; D006801:Humans; D008297:Male
chemical_list: D001323:Autoantibodies; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen