Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation

• Published in: Gut Vol. 55; no. 6; pp. 863 - 868
• Main Authors: Tapirdamaz, Ö, Pravica, V, Metselaar, H J, Hansen, B, Moons, L, van Meurs, J B J, Hutchinson, I V, Shaw, J, Agarwal, K, Adams, D H, Day, C P, Kwekkeboom, J
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.06.2006; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Acute Disease; Antigens; Antigens, CD; Antigens, Differentiation - genetics; Autoimmune diseases; Biological and medical sciences; Cell cycle; CTLA-4; CTLA-4 Antigen; cytotoxic T lymphocyte antigen 4; Cytotoxicity; Diabetes; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genes; Genetic Predisposition to Disease; Genotype; Graft Rejection - genetics; Growth hormones; haplotype; Haplotypes; HBV; HCV; Hepatitis; hepatitis B virus; hepatitis C virus; HGH; human growth hormone; Humans; Immunoglobulins; Infections; Influence; interleukin; Liver cirrhosis; Liver Disease; Liver diseases; Liver Transplantation; Liver, biliary tract, pancreas, portal circulation, spleen; Lymphocytes; Male; mCTLA-4; Medical sciences; membrane CTLA-4; Patients; PCR; Polymerase chain reaction; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Proportional Hazards Models; rejection; Retrospective Studies; sCTLA-4; single nucleotide polymorphism; SNP; soluble CLTA-4; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; Transplants & implants; Antigen; Rejection; Graft(material); Immunological investigation; Acute; Gastroenterology; T-Lymphocyte; Cytotoxicity; Polymorphism; Liver transplantation
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2005.080937

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.