title: Haplotype analysis in simplex families and novel analytic approaches in a case-control cohort reveal no evidence of association of the CTLA-4 gene with rheumatoid arthritis.
abstract: OBJECTIVE
  Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T cells and is, therefore, a strong candidate susceptibility gene for T cell-mediated autoimmune diseases. The association of CTLA-4 single-nucleotide polymorphisms (SNPs) with rheumatoid arthritis (RA) has been investigated previously, with inconsistent results. Recently, SNPs mapping to the gene (and not previously investigated in RA) have been associated with both type 1 diabetes mellitus and Graves' disease. The aim of this study was to investigate the association of the CTLA-4 polymorphism with RA.
  
  
  METHODS
  Primer extension methods were used to genotype 5 haplotype-tagging SNPs (htSNPs) (-1722 T/C, -1661 A/G, -658 C/T, -319 C/T, and +49 A/G), and the TaqMan 5' allelic discrimination assay was used to genotype an additional 2 SNPs (CT60 and rs1863800) mapping to the CTLA-4 gene. Association to the 5 htSNPs was investigated using the transmission disequilibrium test in RA simplex families (n = 122). Allele frequencies for the htSNPs were also investigated in affected sibling pairs (n = 96) and unrelated controls (n = 173). For the SNPs CT60 and rs1863800, unrelated patients with RA (n = 759) were compared with controls (n = 755).
  
  
  RESULTS
  No evidence for association to single markers or haplotypes of the 5 htSNPs was detected in either RA simplex families or the affected sibling-control cohort. Neither of the 2 SNPs recently associated with Graves' disease showed evidence for association in the unrelated patient-control cohort.
  
  
  CONCLUSIONS
  No evidence for association of CTLA-4 with RA was detected using family or case-control methods.
authors.affiliation: University of Manchester, Manchester, UK. Abarton@fs1.ser.man.ac.uk
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Francine
authors.initials: F
authors.lastname: Jury
authors.forename: Stephen
authors.initials: S
authors.lastname: Eyre
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.forename: Daniel
authors.initials: D
authors.lastname: Ward
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
mesh_terms: D000328:Adult; D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D035781:Siblings
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human