Association of Polymorphisms in T-Cell Activation Costimulatory/Inhibitory Signal Genes With Allograft Kidney Rejection Risk

Abstract

The genes CD28, CD86 and CTLA-4 conform the costimulatory (CD28-CD86) or inhibitory (CTLA-4-CD86) signal in T-cell activation. T-cell immune response has a critical role in allograft rejection, and single nucleotide polymorphisms (SNPs) located in these genes have been widely analyzed with controversial results. We analyzed a group of SNPs located in the three genes: CD28: rs3116496; CD86: rs1129055; and CTLA-4: rs231775 and rs3087243 in a cohort of 632 consecutively recruited kidney transplanted subjects. All polymorphisms were genotyped by TaqMan chemistry and the diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. The analyses showed a statistically significant protective effect to T cell-mediated rejection (TCMR) in carriers of the CTLA-4 rs3087243*G allele, especially in patients with TCMR Banff ≥2 in the overall cohort and in patients without thymoglobulin induction therapy. Both associations were corroborated as independent factors in the multivariate analysis. Interestingly, associations with rejection were not found for any SNP in patients with thymoglobulin induction therapy. As expected, considering the major role of these genes in T-cell activation, no effect was observed for antibody-mediated rejection (ABMR). In conclusion, the SNP rs3087243 located in the CTLA-4 gene may be considered a useful independent biomarker for TCMR risk especially for severe TCMR in patients who did no received thymoglobulin induction therapy.

Impact of CD 28, CD86, CTLA-4 and PD-1 genes polymorphisms on acute renal allograft rejection and graft survival among Egyptian recipients

“…Our findings suggest that CD 86 gene +1057G>A polymorphism didn`t show a statistically significant association with AR. In agreement with our results, CD 86 gene rs1129055 and CD 28 gene rs3116496 polymorphism were reported to have non-significant association with AR either in the dominant or in the recessive models 22 . However, Han et al, reviewed three studies (234 cases and 411 controls) to define the relationship between the CD86 +1057G/A polymorphism and allograft rejection and reported a significant association between CD86 +1057G/A polymorphism and reduced AR in the dominant genetic model (A/A or A/G vs. G/G) 4 .…”

“…Our results showed that AG genotype of CTLA-4 rs3087243 SNP was the most common genotype among no rejection group and proved a protective effect against AR and this finding came in agreement with the known inhibitory effect of CTLA-4 on T cell activation and so protection against kidney allograft rejection. Our combined results were similar to a cohort of 632 kidney transplant patients who showed a protection against kidney transplant rejection among carriers of the CTLA-4 +6230 G allele which is proved by detecting lower levels of soluble cytotoxic T lymphocyte antigen-4 micro RNA (sCTLA-4 mRNA) 22 . In deceased kidney transplantation, a retrospective study examining 72 deceased donor derived kidney transplant recipients who completed 6 months of follow up post transplantation, reported a significant higher incidence of CT60 A/A genotype in AR group compared with no rejection group (29.7% vs 8.6%; P = 0.035; OR = 4.51) and a higher incidence of CT60 A/G genotype in the no rejection group 27 .…”

“…Taken together, our results came in agreement with a cohort of 314 Caucasian allograft recipients who were followed up for a median time of 97.5 months and showed no relationship between the same allele variants and AR or graft function either in univariate or multivariate analyses 6 . The same findings were obtained with regard to the lack of relationship between rs3116496— CD28 and AR 22 . Moreover, with deceased donor transplants, the same outcome was obtained with no defined clear association between variations in CD 28 gene SNP and AR 18 .…”

“…Also the type of kidney donor whether deceased or living together with the type of induction therapy may have an influence on gene expression, for example one study reported a statistically significant association between patients carrying CTLA-4 +49 AA genotype and lower AR episodes in transplanted recipients who received their kidneys from a living related donor while this association disappeared when compared to another group of transplanted recipients who received their kidneys from a cadaveric unrelated donors 21 . This observation was confirmed by other researchers who showed that in patients receiving thymoglobulin induction therapy, correlations with rejection were not identified for any SNP even for those showed initial significance 22 .…”

“…The disparities in outcomes between studies could be attributed to their small sample size, with just a small number of patients participating 4 . Other considerations include the prior research subjects' heterogeneity in terms of race, which may alter genetic expression 20 , the type of donors whether living or deceased 21 and the type of induction therapy 22 .…”