FKBP1A rs6041749 polymorphism is associated with allograft function in renal transplant patients.

AIM: To investigate the potential impact of single-nucleotide polymorphisms (SNPs) in the FK506-binding protein (FKBP)-calcineurin (CaN)-nuclear factor of activated T cells (NFAT) signaling pathway on the efficacy and safety of tacrolimus (TAC) in Chinese renal transplant patients. METHODS: Seventy-seven tag SNPs were detected in 146 patients who were on TAC-based maintenance immunosuppression and who followed up for at least 2 years. The relationships of these polymorphisms with clinical outcomes such as acute rejection, acute nephrotoxicity, pneumonia, and estimated glomerular filtration rate (eGFR) were explored. For the FKBP1A rs6041749 polymorphism, which has a significant association with renal function over time, a preliminary functional analysis was performed using a dual-luciferase reporter gene system. RESULTS: The patients with FKBP1A rs6041749 TT genotype had a more stable eGFR level than CC and CT carriers (P = 2.08 × 10-8) during the 2 years following transplantation. Dual-luciferase reporter assay results showed that the rs6041749 C variant could enhance the relative luciferase activity compared with the T variant, which indicated that the rs6041749 C allele may increase the FKBP1A gene transcription. In addition, we did not find any association between these genetic variants and the risk of acute rejection, acute nephrotoxicity, and pneumonia in renal transplant patients receiving TAC-based immunosuppression. CONCLUSIONS: FKBP1A rs6041749 C allele carriers are at higher risk for eGFR deterioration. The variant might serve as a biomarker to predict allograft function in renal transplant patients.

CYP3A5 and CYP3A7 genetic polymorphisms affect tacrolimus concentration in pediatric patients with nephrotic range proteinuria.

PURPOSE: The purpose of this study was to investigate the potential impact of CYP3A4, CYP3A5, and CYP3A7 polymorphisms on the concentration and efficacy of tacrolimus in a cohort of pediatric patients with nephrotic range proteinuria. METHODS: Genetic variants including CYP3A5*3 (rs776746), CYP3A4*1G (rs2242480), rs4646437, and CYP3A7 rs2257401 and rs10211 were detected in 70 pediatric patients with nephrotic range proteinuria. The relationships of dose-adjusted trough concentration (C0) of tacrolimus with corresponding genotypes were investigated. RESULTS: The tacrolimus concentration in patients without CYP3A5*3 A allele was 94% higher than those with A allele (90.7 vs 54.2, P = 0.00006). The CYP3A7 rs2257401 was also associated with the concentration of tacrolimus. The C allele carriers had an obviously lower C0 than the non-carriers (62.4 vs 90.7, P = 0.001). In addition, there were significant differences in tacrolimus concentration among CYP3A7 rs10211 G carriers and non-carriers; the latter had an almost twofold C0 of the former (101.8 vs 59.6, P = 0.0004). CONCLUSIONS: Our study demonstrated the associations between CYP3A5*3, CYP3A7 rs2257401 and rs10211, and tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Children with CYP3A5*3 A, CYP3A7 rs2257401 C, and rs10211 G alleles might need a higher dose of tacrolimus.

FOXP3 rs3761548 polymorphism is associated with tacrolimus-induced acute nephrotoxicity in renal transplant patients.

PURPOSE: The purpose of this study was to investigate the potential impact of FOXP3 and CCDC22 gene polymorphisms on efficacy and safety of tacrolimus (TAC) in renal transplant patients. METHODS: Genetic polymorphisms were detected in 114 Chinese renal transplant patients who were on TAC-based maintenance immunosuppression and were followed up for at least 2 years. The relationships between FOXP3 rs3761547, rs3761548, rs3761549, rs2232365, rs2280883, and CCDC22 rs2294021 polymorphisms and clinical outcomes such as acute rejection, TAC-induced acute nephrotoxicity, and pneumonia were investigated by using Kaplan-Meier estimates and multivariate Cox regression analysis. The influence of these gene polymorphisms on the change in estimated glomerular filtration rate over time was evaluated by linear mixed model. RESULTS: Patients with FOXP3 rs3761548 AA and AC genotypes had a 10-fold higher risk for TAC-induced acute nephrotoxicity than those with CC genotype. We did not find any association between other genetic variants and TAC-related outcomes in renal transplant patients. CONCLUSIONS: Our study demonstrated the TAC-induced acute nephrotoxicity was associated with FOXP3 rs3761548 polymorphism in renal transplant patients. FOXP3 rs3761548 might serve as a biomarker to prevent TAC toxicity and help progression toward individualized therapy of TAC.

TLR10 genotypes affect long-term graft function in tacrolimus-treated solid organ transplant recipients.

The present study was conducted to investigate the relationship between single nucleotide polymorphisms (SNPs) in TLR10 and the clinical outcomes of renal transplant patients who took tacrolimus (TAC) as an immunosuppressant, and further confirmed the results in liver transplant patients. A total of 172 renal transplant patients and 145 pairs of liver transplant recipients and donors were included. Nineteen SNPs of TLR10 gene were detected by matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS). The associations of recipient SNPs with TAC-related clinical outcomes were explored in renal transplant recipients. The relationship between recipient and donor SNPs and the clinical outcomes of liver transplant patients were investigated to confirm the results. Three SNPs (rs28393318, rs11466655 and rs11096957) in renal transplant recipients were found to influence the graft function after transplantation (P = 0.00003, 0.001 and 0.000003, respectively). The recipient rs11096957 was also found to affect the TBil, and DBil levels in liver transplant recipients (P = 0.001 and 0.002). In this study, we identified significant association signals from TLR10 polymorphisms with clinical outcomes in TAC-treated transplant patients in a Chinese Han-based sample. We provide some evidence for the effect between rs11096957 in TLR10 gene on the graft functions in both renal and liver transplantation.

CYP3A7, CYP3A4, and CYP3A5 genetic polymorphisms in recipients rather than donors influence tacrolimus concentrations in the early stages after liver transplantation.

AIM: The purpose of this study was to investigate the effect of CYP3A7, CYP3A4, and CYP3A5 genetic polymorphisms in liver transplant recipients and donors on tacrolimus concentrations in the early stages after liver transplantation. METHODS: One hundred and thirty-eight liver transplant recipients and matched donors were genotyped for CYP3A7 (rs10211 and rs2257401), CYP3A4 (rs4646437 and rs2242480), and CYP3A5*3 (rs776746) polymorphisms. The relationships between dose-adjusted trough concentrations (C0/D) of tacrolimus and corresponding genotypes were investigated. RESULTS: Recipient CYP3A polymorphisms were associated with tacrolimus concentrations. The CYP3A7 rs10211 AA carriers (186.2 vs 90.5, p < 0.001), CYP3A4 rs4646437 CC carriers (184.0 vs 88.8, p < 0.001), CYP3A4*1G rs2242480 CC carriers (189.8 vs 99.7, p < 0.001), and CYP3A5*3 rs776746 GG carriers (197.3 vs 86.0, p < 0.001) had an almost twofold increase in the tacrolimus C0/D compared to that of the non-carriers. We further investigated the effect of the combination of recipient (intestinal) and donor (hepatic) genotypes on tacrolimus concentrations. Regardless of the genotype of the matched donor, CYP3A7 rs10211, CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746) polymorphisms of recipients could affect tacrolimus concentrations. For the CYP3A4 rs4646437 polymorphisms, when the donor carried CYP3A4 rs4646437 CC, the recipient CYP3A4 rs4646437 polymorphism was associated with the C0/D of tacrolimus, and when the donor carried CYP3A4 rs4646437 CT/TT genotype, the recipient CYP3A4 rs4646437 polymorphism also affected on tacrolimus C0/D, although the effect was not significant. CONCLUSION: The large inter-individual variation in tacrolimus concentrations in the early stages after liver transplantation is influenced by genetic polymorphisms of CYP3A7, CYP3A4, and CYP3A5. Recipient (intestinal) CYP3A7, CYP3A4, and CYP3A5 polymorphisms seem to contribute more to such variation than donors. Therefore, the detection of CYP3A polymorphisms in recipients could help to predict the tacrolimus starting dose in the early stages after liver transplantation.

FKBP-CaN-NFAT pathway polymorphisms selected by in silico biological function prediction are associated with tacrolimus efficacy in renal transplant patients.

AIM: The aim of the present study was to investigate the potential effects of genetic variations in the FKBP-CaN-NFAT pathway on clinical events associated with tacrolimus efficacy in Chinese renal transplant patients. METHODS: One hundred and forty Chinese renal transplant patients of Han ethnicity with over five years of follow-up were enrolled in our study. A pool of single nucleotide polymorphisms (SNPs) (1284 SNPs) was extracted from the Ensembl database according to chromosomal regions of the candidate genes. Next, 109 SNPs were screened out from this pool using multiple bioinformatics tools for subsequent genotyping using the MALDI-TOF-MS method. The associations of these candidate SNPs with acute rejection, nephrotoxicity, pneumonia and post-transplant estimated glomerular filtration rate (eGFR) were explored. RESULTS: Fourty-four SNPs were found to be associated with tacrolimus-related clinical drug response. Specifically, eight SNPs were associated with the incidence of biopsy-proven acute rejection, four SNPs were associated with the rate of nephrotoxicity, 16 SNPs were correlated with the onset of pneumonia, and 26 SNPs were found to significantly influence post-transplant eGFR trend. An elaborate scoring system was implemented to prioritize the validation of these potentially causal SNPs. In particular, NFATC2 rs150348438 (G>T) performed well during integrative scoring (Ptotal=23.8) and was significantly associated with the occurrence of pneumonia (P = 0.0035, HR=0.91, 95% CI=0.85-0.97) and post-transplant eGFR levels (P = 0.000003). CONCLUSIONS: NFATC2 rs150348438, rs6013219, rs1052653, and NFATC1 rs754093, ranking high in scoring, significantly affected the post-transplant eGFR and the incidence of pneumonia, acute rejection, and nephrotoxicity in renal transplant patients taking tacrolimus. Those SNPs may alter the expression and regulation of FKBP-CaN-NFAT pathway by influencing transcription regulation, mature mRNA degradation and RNA splicing, or protein coding. Critical SNPs of high ranking may serve as PD-associated pharmacogenetic biomarkers indicating individual response variability of TAC, and thus aid the clinical management of renal transplant patients.

FOXP3 rs3761549 polymorphism predicts long-term renal allograft function in patients receiving cyclosporine-based immunosuppressive regimen.

AIM: The present study was conducted to determine the effect of FOXP3 single nucleotide polymorphisms (SNPs) on clinical outcomes in CsA-treated renal transplant patients. METHODS: A total of 166 renal transplant patients with at least 5years of follow-up were included. SNPs of FOXP3 gene (rs3761547, rs3761548, rs3761549, rs2232365 and rs2280883) were detected by Taqman probe technique. The associations of SNPs with acute rejection, CsA-induced nephrotoxicity, pneumonia and post-transplantation estimated glomerular filtration rate (eGFR) were explored. RESULTS: Patients with rs3761549 T/TT genotype showed a more rapid decline in the eGFR level during the 5years following transplantation than those with the C/CC genotype (24.0% vs. 6.3%, P=0.004). All the SNPs and site-site interaction were not related to the occurrence of acute rejection, nephrotoxicity, and pneumonia. CONCLUSIONS: FOXP3 rs3761549 was significantly correlated with the renal allograft function. It could be used to predict and improve the outcome of renal transplant patients taking CsA as an immunosuppressant.

NFATC1 genotypes affect acute rejection and long-term graft function in cyclosporine-treated renal transplant recipients.

AIM: To investigate the effects of SNPs in the cyclophilin A/calcineurin/nuclear factor of activated T-cells (NFATs) pathway genes (PPIA, PPP3CB, PPP3R1, NFATC1 and NFATC2) on cyclosporine (CsA) efficacy in renal transplant recipients. MATERIALS & METHODS: Seventy-six tag SNPs were detected in 155 CsA-treated renal recipients with at least a 5-year follow-up. The associations of SNPs with acute rejection, nephrotoxicity, pneumonia and estimated glomerular filtration rate post transplant were explored. RESULTS: NFATC1 rs3894049 GC was a risk factor for acute rejection compared with CC carriers (p = 0.0005). NFATC1 rs2280055 TT carriers had a more stable estimated glomerular filtration rate level than CC (p = 0.0004). CONCLUSION: Detecting NFATC1 polymorphisms could help predict CsA efficacy in renal transplant patients.