The influence of CTLA-4 gene polymorphisms on liver transplant outcomes

✍ Scribed by James D. Perkins

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 80 KB
• Volume: 12
• Category: Article
• ISSN: 1527-6465
• DOI: 10.1002/lt.20923

✦ Synopsis

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 ϩ49A/G single nucleotide polymorphism (SNP) influences expression of mCTLA-4; ϩ6230G/A SNP affects the production of soluble sCTLA-4. Aim: To examine whether these functional SNPs influence the rate of rejection after liver transplantation. Patients and methods: Liver graft recipients (n ϭ 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: ϩ49A/ϩ6230A, ϩ49A/ϩ6230G, and ϩ49G/ϩ6230G. The ϩ49A/ϩ6230G haplotype was significantly and dose dependently associated with acute rejection (p ϭ 0.01). Of the demographic factors tested, only underlying liver disease was significantly associated with rejection. Adjusted for underlying liver disease, each additional ϩ49A/ϩ6230G haplotype allele resulted in a significantly higher risk of acute rejection (risk ratio 1.34 (95% confidence interval 1.04-1.72); p ϭ 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 ϩ49A/ϩ6230G 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.