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Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation
  1. Ö Tapirdamaz1,
  2. V Pravica2,
  3. H J Metselaar1,
  4. B Hansen3,
  5. L Moons1,
  6. J B J van Meurs4,
  7. I V Hutchinson2,
  8. J Shaw5,
  9. K Agarwal6,
  10. D H Adams5,
  11. C P Day6,
  12. J Kwekkeboom1
  1. 1Departments of Gastroenterology and Hepatology, University Medical Centre Rotterdam, the Netherlands
  2. 2Immunology Research Group, University of Manchester, UK
  3. 3Departments of Epidemiology and Biostatistics, University Medical Centre Rotterdam, the Netherlands, and Departments of Gastroenterology and Hepatology, University Medical Centre Rotterdam, the Netherlands
  4. 4Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, the Netherlands
  5. 5Liver Research Laboratories, MRC Centre for Immune Regulation, 5th Floor Institute of Biomedical Research, University of Birmingham Medical School, UK
  6. 6Centre for Liver Research, University of Newcastle upon Tyne, UK
  1. Correspondence to:
    Dr J Kwekkeboom
    Laboratory for Gastroenterology and Hepatology, Room L-455, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, the Netherlands; j.kwekkeboom{at}


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.

Aim: To examine whether these functional SNPs influence the rate of rejection after liver transplantation.

Patients and 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.

Conclusion: 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.

  • CTLA-4, cytotoxic T lymphocyte antigen 4
  • mCTLA-4, membrane CTLA-4
  • sCTLA-4, soluble CLTA-4
  • SNP, single nucleotide polymorphism
  • HGH, human growth hormone
  • IL, interleukin
  • HBV, hepatitis B virus
  • HCV, hepatitis C virus
  • PCR, polymerase chain reaction
  • cytotoxic T lymphocyte antigen 4
  • liver transplantation
  • rejection
  • haplotype
  • single nucleotide polymorphism

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  • Published online first 18 November 2005

  • Conflict of interest: None declared.

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