title: Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation.
abstract: BACKGROUND
  The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene encodes for a membrane bound (mCTLA-4) and a soluble (sCTLA-4) isoform, which are both involved in regulation of T cell function. The CTLA-4 +49A/G single nucleotide polymorphism (SNP) influences expression of mCTLA-4; +6230G/A SNP affects the production of sCTLA-4.
  
  
  OBJECTIVE
  To examine whether these functional SNPs influence the rate of rejection after liver transplantation.
  
  
  METHODS
  Liver graft recipients (n = 483) were genotyped for both SNPs, and haplotypes were reconstructed. Association with rejection was tested by the log rank test using the Kaplan-Meier method with time to the first acute rejection episode as outcome. Multiple analysis of SNPs together with demographic factors was performed by Cox regression.
  
  
  RESULTS
  Three haplotypes were observed in the cohort: +49A/+6230A, +49A/+6230G, and +49G/+6230G. The +49A/+6230G haplotype was significantly and dose dependently associated with acute rejection (p = 0.01). Of the demographic factors tested, only underlying liver disease was significantly associated with rejection. Adjusted for underlying liver disease, each additional +49A/+6230G haplotype allele resulted in a significantly higher risk of acute rejection (risk ratio 1.34 (95% confidence interval 1.04-1.72); p = 0.02). Patients who lacked this haplotype had the lowest, carriers an intermediate, and homozygotes the highest risk of acute rejection.
  
  
  CONCLUSIONS
  The CTLA-4 +49A/+6230G haplotype, which encodes for normal mCTLA-4 expression but reduced sCTLA-4 production, is a co-dominant risk allele for acute rejection after clinical liver transplantation. This implies that even under immunosuppression, CTLA-4 is critically involved in the regulation of the human immune response to allogeneic grafts.
authors.affiliation: Department of Gastroenterology, University Medical Centre, the Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Tapirdamaz
authors.forename: V
authors.initials: V
authors.lastname: Pravica
authors.forename: H J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: B
authors.initials: B
authors.lastname: Hansen
authors.forename: L
authors.initials: L
authors.lastname: Moons
authors.forename: J B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: I V
authors.initials: IV
authors.lastname: Hutchinson
authors.forename: J
authors.initials: J
authors.lastname: Shaw
authors.forename: K
authors.initials: K
authors.lastname: Agarwal
authors.forename: D H
authors.initials: DH
authors.lastname: Adams
authors.forename: C P
authors.initials: CP
authors.lastname: Day
authors.forename: J
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D000208:Acute Disease; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012189:Retrospective Studies
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human