title: CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis.
abstract: OBJECTIVE
  Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease thought to develop through a complex interaction of genetic and environmental factors. It is characterised by T-cell-mediated non-suppurative destructive cholangitis. We have studied the polymorphic cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene, which encodes a molecule that is a vital negative regulator of T-cell activation, as a candidate susceptibility locus for PBC. This gene on chromosome 2q33 (designated IDDM12) is associated with susceptibility to both type 1 diabetes and autoimmune thyroid disease.
  
  
  METHODS
  The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alanine, respectively) was genotyped via polymerase chain reaction in 200 Caucasoid PBC patients and 200 non-related geographically matched Caucasoid controls.
  
  
  RESULTS
  There was significant overrepresentation of the G/A and G/G genotypes in PBC patients compared to controls (G/A 53% vs 40%; G/G 18.5% vs 10.5%, Odds Ratio (OR)=2.45 [95% CI 1.6-3.7], p=0.00006, chi2=19.4). Likewise, there was a significant difference in allele frequencies (G encoding alanine at codon 17, PBC 0.45 vs controls 0.305: OR=1.9 [1.4-2.5], p<0.0002). This association remained significant (p=0.00027) when patients with autoimmune thyroid disease were excluded from the analysis.
  
  
  CONCLUSIONS
  The CTLA-4 exon 1 polymorphism is the first non-major histocompatibility complex gene to be identified as a susceptibility locus for PBC. Our data support the hypothesis that clinically distinct autoimmune disease may be controlled by a common set of susceptibility genes.
authors.affiliation: Centre for Liver Research, University of Newcastle, Newcastle Upon Tyne, UK.
authors.forename: K
authors.initials: K
authors.lastname: Agarwal
authors.forename: D E
authors.initials: DE
authors.lastname: Jones
authors.forename: A K
authors.initials: AK
authors.lastname: Daly
authors.forename: O F
authors.initials: OF
authors.lastname: James
authors.forename: B
authors.initials: B
authors.lastname: Vaidya
authors.forename: S
authors.initials: S
authors.lastname: Pearce
authors.forename: M F
authors.initials: MF
authors.lastname: Bassendine
mesh_terms: D000069594:Abatacept; D000368:Aged; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018796:Immunoconjugates; D008105:Liver Cirrhosis, Biliary / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept