title: Genotypes in relation to phenotypic appearance and exposure to environmental factors in Graves' hyperthyroidism.
abstract: BACKGROUND
  Genetic polymorphisms and environmental factors are both involved in the pathogenesis of Graves' disease, but their interaction and effect on Graves' phenotypes have scarcely been investigated.
  
  
  OBJECTIVE
  To test the hypothesis that subjects with susceptibility genotypes develop more severe Graves' hyperthyroidism at a younger age and after less exposure to environmental factors, with attention to gender differences.
  
  
  METHODS
  A prospective observational multicenter study in 205 adult Caucasian patients with untreated first episode of Graves' hyperthyroidism.
  
  
  METHODS
  Evaluation of genotypes (HLA DRB1*03, DQA1*05, DQB1*02; CTLA4 49A/G, CT60 A/G; PTPN22 C/T) in relation to phenotypes (age, sex, severity (clinical, biochemical, and immunological)) of hyperthyroidism and environmental factors (smoking, stress questionnaires).
  
  
  RESULTS
  G-alleles in CTLA4 single nucleotide polymorphisms were dose-dependently associated with younger age at the time of diagnosis and less exposure to daily hassles. In gender-specific analysis, this association is enhanced in men and attenuated in women. Males (but not females) in HLA linkage disequilibrium had more severe (biochemical and immunological) hyperthyroidism and a tendency to younger age at diagnosis, compared with those not in linkage disequilibrium.
  
  
  CONCLUSIONS
  Graves' hyperthyroidism occurs at a younger age with less exposure to environmental factors in subjects carrying susceptibility genotypes. The impact of genotypes seems to be greater in males than in females.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. x.g.vos@amc.nl
authors.forename: Xander G
authors.initials: XG
authors.lastname: Vos
authors.forename: Erik
authors.initials: E
authors.lastname: Endert
authors.forename: Jan G P
authors.initials: JG
authors.lastname: Tijssen
authors.forename: Wilmar M
authors.initials: WM
authors.lastname: Wiersinga
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D060908:CTLA-4 Antigen / Q000235:genetics; D005260:Female; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D059848:HLA-DQ alpha-Chains / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D012737:Sex Factors; D055815:Young Adult
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D059811:HLA-DRB1 Chains; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22