Abstract
BackgroundAcute rejection (AR) is a common complication of kidney transplantation. Nuclear factors of activated T cells (NFATs) are transcription factors involved in the activation of T lymphocytes, but their association with AR is unclear.MethodsThis retrospective, case–control study included 200 renal transplant recipients who were divided into the AR group (n = 69) and stable group (n = 131). Their blood samples were collected, and DNA was extracted from the whole blood. High-throughput next-generation sequencing was used to identify single nucleotide polymorphisms (SNPs) of the NFATC2 and NFATC4 genes. The correlation of these SNPs with AR was determined by logistic analysis.ResultsSeventy-one SNPs of the NFATC2 and NFATC4 genes were identified by the sequencing and Hardy–Weinberg equilibrium analyses. After adjusting for age, gender and immunosuppressive protocols, 27 SNPs were correlated with AR, of which the SNP rs2426295 of the NFATC2 gene showed a significant correlation with AR in the HET model (AA vs. AC: OR = 0.43, 95% CI = 0.19–0.98, P = 0.045), but no significant NFATC4 SNPs were identified.ConclusionsOur study shows that the rs2426295 variant of the NFATC2 gene is significantly associated with the occurrence of AR following kidney transplantation. And patients with AA genotypes in rs2426295 are inclined to suffer from AR pathogenesis.
Highlights
Kidney transplantation is the optimal and most cost-effective method of renal replacement therapy for patients with endstage renal diseases [1, 2]
Studies have shown that NFATC2 mRNA is expressed mainly in peripheral lymphoid tissues such as the spleen and peripheral blood lymphocytes, and that NFATC4 mRNA is expressed at high levels in the thymus; these findings indicate the crucial role of NFATC2 and NFATC4 in T-cell development [13, 20]
After adjustment for age, gender and immunosuppressive protocols in all five models, we found that rs2426295 on the NFATC2 gene was significantly correlated with the risk of Acute rejection (AR) episodes following kidney transplantation in the HET model (AA vs. AC: Odds ratios (ORs) = 0.43, 95% confidence intervals (95% CIs) = 0.19–0.98, P = 0.045, Table 2)
Summary
Kidney transplantation is the optimal and most cost-effective method of renal replacement therapy for patients with endstage renal diseases [1, 2]. Its wide applicability is limited by various complications, such as acute rejection (AR), chronic allograft dysfunction and immunosuppressive agent-related nephrotoxicity Among these complications, AR is an important cause of graft loss that may occur at any time point in the lifetime of renal transplant recipients, independent of age and gender [3]. Calcineurin modulates the translocation of NFAT proteins from the cytoplasm to the nucleus of activated cells by interacting with an N-terminal regulatory domain that is conserved in the NFAT family [15,16,17] Classic immunosuppressive agents, such as cyclosporine A (CsA) and tacrolimus, inhibit the action of calcineurin and thereby prevent the de-phosphorylation of NFATs and their subsequent nuclear translocation [18, 19].
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