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The influence of CTLA‐4 gene polymorphisms on liver transplant outcomes
Author(s) -
Perkins James D.
Publication year - 2006
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.20923
Subject(s) - medicine , liver transplantation , ctla 4 , gene , oncology , immunology , transplantation , genetics , immune system , t cell , biology
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 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 = 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.