Influence of Cytotoxic T-Lymphocyte Antigen-4 Polymorphisms on Acute Rejection Onset of Cadaveric Renal Transplants

We retrospectively examined in cadaveric renal transplants the association between acute rejection episodes (ARE) and single nucleotide polymorphisms (SNPs) localized in the cytotoxic T-lymphocyte antigen (CTLA)-4 promoter, −1147T/C and −318C/T, in exon 1 +49A/G and within the 3′ untranslated region (UTR) CT60G/A. Each one of these SNPs may influence the cell surface expression of the CTLA-4 molecule. Seventy-two cadaveric renal transplant recipients with at least 6 month's follow-up were genotyped for CTLA-4 dimorphisms using direct sequencing of specific polymerase chain reaction products. Allele frequencies in both groups of patients with or without acute rejection (ARE and non-ARE) did not show significant differences in various nucleotide positions. At the level of genotype frequency we first noted a positive association to acute rejection of G/G genotypes (ARE af = 14.7%, non-ARE af = 5.9%) for the +49 (cod. 17), which was associated with decreased expression of the CTLA-4 full-length molecule. In contrast, the AG genotype seemed to be protective (61.8% vs 32.4%, P = .028; odds ratio [OR] = 0.2961). Regarding the CT60G/A dimorphism, noteworthy was the identification of a significantly higher incidence of CT60 A/A genotype in ARE compared with non-ARE group (29.7% vs 8.6%; Yates P = .035; OR = 4.51). Such association of protective AA genotype with ARE, as observed also in autoimmunity, was associated with an increased level of sCTLA-4 induced by the polymorphism, which blocks B7–flCTLA-4 interactions, enhancing T-cell reactivity by preventing transduction of inhibitory signals. Considering the various polymorphic sites in the haplotype, we observed a significant increase in ARE among patients of the CTLA4 +49A/CT60A (HF = 51.5% vs 29.5%; P = .014; OR = 2.545) and a reduction among the +49A/CT60G (17.6% vs 33.8%; P = .04; OR = 0.4193) 2-loci haplotype, As regards the −1147/−318/+49/CT60 CTLA-4 4-loci haplotypes, we observed a significantly higher frequency of the CCAA haplotype in ARE patients comparison with those free of rejection (HF = 51.8% vs 31.1%, P = .046 OR = 2.363). These findings are consistent with those observed in allogeneic stem cell transplantation, wherein patients with CT60 AA showed a major incidence of graft-versus-host disease. An association of protective AA genotype with ARE, as observed also in autoimmunity was associated with an increased level of sCTLA-4 induced by this polymorphism, which blocking the B7–flCTLA-4 interaction, would enhance T-cell reactivity by preventing transduction of inhibitory signals.