title: CTLA4 gene and Graves' disease: association of Graves' disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism.
abstract: OBJECTIVE
  Recent studies have shown that Graves' disease (GD) is linked to and associated with alleles of the cytotoxic T lymphocyte antigen-4 (CTLA4) locus. However, the true pathogenic polymorphism(s) at this locus remains uncertain. Moreover, the association studies of the promoter CTLA4(-318)C/T polymorphism in white GD populations have produced conflicting results. Therefore, we have analysed three CTLA4 single nucleotide polymorphisms, including promoter CTLA4(-318)C/T, exon 1 CTLA4(49)A/G and intron 1 CTLA4(1822)C/T in our GD cohort from the UK.
  
  
  METHODS
  We studied 301 white patients with GD and 349 healthy ethnically matched local controls. Amongst GD probands, 129 had significant thyroid-associated orbitopathy (TAO; NOSPECS class III or worse). The CTLA4(-318)C/T, CTLA4(49)A/G and CTLA4(1822)C/T polymorphisms were genotyped by using the restriction enzymes MseI, Bst71I and HaeIII, respectively.
  
  
  RESULTS
  We found no association between GD and alleles of CTLA4(-318)C/T. GD was found to be associated with the G allele of CTLA4(49)A/G[P = 5.9 x 10(-6), odds ratio (OR) 1.65] and the T allele of CTLA4(1822)C/T (P = 7.7 x 10(-6), OR 1.64). The frequencies of these alleles were significantly higher in GD probands with significant TAO than in those without TAO (G allele: P = 0.001, OR 1.68; T allele: P = 0.001, OR 1.70).
  
  
  CONCLUSIONS
  The promoter CTLA4(-318)C/T polymorphism is not in linkage disequilibrium with the pathogenic polymorphism(s) at the CTLA4 locus. The alleles of both the exon 1 CTLA4(49)A/G and the intron 1 CTLA4(1822)C/T polymorphisms are associated with GD, which is stronger in patients with TAO.
authors.affiliation: Department of Endocrinology, University of Newcastle, Newcastle upon Tyne, UK. bvaidya@hgmp.mrc.ac.uk
authors.forename: B
authors.initials: B
authors.lastname: Vaidya
authors.forename: E J C
authors.initials: EJ
authors.lastname: Oakes
authors.forename: H
authors.initials: H
authors.lastname: Imrie
authors.forename: A J
authors.initials: AJ
authors.lastname: Dickinson
authors.forename: P
authors.initials: P
authors.lastname: Perros
authors.forename: P
authors.initials: P
authors.lastname: Kendall-Taylor
authors.forename: S H S
authors.initials: SH
authors.lastname: Pearce
mesh_terms: D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D018796:Immunoconjugates; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept