The Impact of Costimulatory Molecule Gene Polymorphisms on Clinical Outcomes in Liver Transplantation

Abstract

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 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.

Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with B-cell chronic lymphocytic leukemia in the Polish population

“…On the other hand, such results were not reported in colorectal cancer [40,41]. The opposite results were obtained in the majority of studies devoted to autoimmunological disorders, in which the CTLA-4c.49AϾG [G] allele was associated with susceptibility to disease [13,30,42,43].…”

Association of genetic variation in co-stimulatory molecule genes with outcome of liver transplant in Iranian patients

“…Marder et al studied the association of CTLA4 318, 49 and CD28 gene polymorphisms with liver transplant outcomes. Although no significant differences were observed between CTLA4 318 and CD28, significant differences between CTLA4 49 and liver transplant outcomes were detected (Marder et al, 2003b). In a previous study, we reported that there is a significant association between IFN-γ, IL-6 polymorphism liver, and kidney transplant outcome (Karimi et al, 2011(Karimi et al, , 2012.…”

“…In animal models, preventing CD28, CD80, and CD86 co-stimulation by targeted deletion or treating monoclonal antibodies against these receptors, could significantly improve allograft outcomes (Marder et al, 2003b). Also, several studies have evidenced the role of CTLA4-Ig as a promoter of graft survival (Sayegh and Turka, 1998).…”

Characterization of CD28, CTLA4, and ICOS Polymorphisms in Three Brazilian Ethnic Groups

“…However, because CD28, CTLA4,and ICOS loci are in close proximity, possible linkage disequilibrium (LD) between the alleles of these genes should be taken into account. Another important point to consider in these association studies is the ethnic homogeneity of the groups being compared because differences in allelic frequencies have been observed among different ethnic groups [5,6].…”