The impact of costimulatory molecule gene polymorphisms on clinical outcomes in liver transplantation.
CTLA-4 and CD28 deliver opposing signals for T-cell proliferation. We examined single nucleotide polymorphisms (SNPs) CTLA-4 -318C/T and CD28 IVS3 +17T/C for associations with acute rejection in liver transplant recipients. These and two other polymorphisms in CTLA-4 [microsatellite polymorphism +642(AT)n and SNP +49 A/G] were also analyzed for influence on graft survival. Two hundred and eleven liver transplant recipient genotypes were determined by direct sequencing or restriction fragment length polymorphism analysis of PCR-amplified genomic DNA. Mean graft survival for patients with the GG genotype of CTLA-4 +49 A/G was 58.5 +/- 6.0 months compared with 70.3 +/- 4.0 months and 73.8 +/- 2.8 months for the AA and AG genotypes, respectively (p = 0.0055). This is in support of previous studies suggesting decreased CTLA-4 function and increased incidence of autoimmune disease for this genotype. The 92-, 94-, and 100-bp alleles of CTLA-4 +642(AT)n occurred more often in African-American transplant recipients and were associated with decreased graft survival (p = 0.0001 and 0.007, respectively) but the independence of these variables could not be established. No associations with acute rejection or graft survival were found for CTLA-4 -318C/T or CD28 IVS3 +17T/C. The described associations between CTLA-4 gene polymorphisms and transplant outcomes provide the foundation for further investigations leading to genetic risk stratification for transplant recipients.
Marder
Brad A
BA
Division of Nephrology, Mount Sinai School of Medicine, New York, NY, USA. brad.marder@mssm.edu
Schröppel
Bernd
B
Lin
Marvin
M
Schiano
Thomas
T
Parekh
Rulan
R
Tomer
Yaron
Y
Murphy
Barbara
B
D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001483:Base Sequence; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D017931:DNA Primers; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D016031:Liver Transplantation; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017931:DNA Primers