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

Wu, Zhuo; Xu, Qinxia; Qiu, Xiaoyan; Jiao, Zheng; Zhang, Ming; Zhong, Ming

doi:10.1007/s00228-016-2140-z

Cited by 22 publications

(12 citation statements)

References 47 publications

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“…In the present study, female patients with the rs2232365 AA and the rs3761548 AA genotypes had a 1.16‐ and a 1.36‐fold persistent HBV risk than non‐carriers in a recessive model, although this was not significant ( p = 0.68 and 0.38, respectively). There are some studies that revealed no association between these polymorphisms and different diseases in terms of gender groups . These results are consistent with the findings of the present study.…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, patients carrying the rs3761548 AA genotype had a 1.24‐fold higher HBV risk in the co‐dominant model, although this also was not significant ( p = 0.34, OR = 1.24; 95% CI = 0.81–1.86). In the literature, the AA genotype has been indicated to be a risk factor in a few studies . On the other hand, some studies showed an inverse association between different diseases and the rs376148 polymorphism.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Forkhead Box P3 gene polymorphisms in chronic HBV infection

Akgöllü

2020

The Journal of Gene Medicine

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Background: Hepatitis B virus (HBV) infection causes liver failure, liver cirrhosis and hepatocellular carcinoma. The FOXP3 gene polymorphisms, the rs2232365 A/G and the rs3761548 A/C, were identified to be associated with regulatory T cell-mediated immunosuppression. The response to HBV infection may be affected by FOXP3 polymorphisms. The present study aimed to assess the relationship between FOXP3 gene polymorphisms and chronic HBV infection risk. Methods: FOXP3 gene polymorphisms were explored in 237 chronic HBV patients and in 237 individuals with HBV spontaneous clearance using a real-time polymerase chain reaction. Results:The patients with rs2232365 AG and rs3761548 AC genotype had a 1.20and a 1.58-fold greater HBV risk than non-carriers patients, although they were not significant. Moreover, the AA genotypes of both polymorphisms in the males and females had an increased the persistent HBV risk, although this also was not statistically significant. Conclusions:In conclusion, the present study is the first report to demonstrate that these polymorphisms have no effect on the risk of chronic HBV infection. This results suggest that FOXP3 gene polymorphisms and FOXP3 expression should be evaluated together with frequency of regulatory T cells in HBV infection.Evidence has shown that an increased frequency of circulating Treg cells causes the negative regulation of a functional CD8 + T cell response by suppressing the CD4 + T cell response, with consequent development of chronic HBV infection. 9 FOXP3 (Forkhead Box P3), a transcription factor, is a primary protein for the activation and development of Treg cells that have suppressor ability with respect to the immune response. 10 The FOXP3 gene is on chromosome Xp11.23.The FOXP3 gene has functional polymorphic domains located in DNA-binding sites of the promoter region, and their presence may affect FOXP3 gene expression. Accordingly, the activation and development of Treg cells may be impaired. 11,12 These polymorphisms in the promoter of the FOXP3 gene, the rs2232365 A/G and the rs3761548 A/C, have been associated with various diseases, including autism, 12 allergic rhinitis, 13 vitiligo, 14 multiple sclerosis, 15 hepatocellular carcinoma and non-small cell lung cancer. 16 However, to date, there are no studies available concerning the influence of the FOXP3 polymorphisms on CHB infection. Although a few important studies have investigated FOXP3 expression in HBV infection and HBVrelated diseases, FOXP3 gene polymorphisms have not yet been investigated in HBV infection. 17-19 The presernt study aimed to clarify the relationship between CHB infection risk and FOXP3 gene (rs2232365 A/G, rs3761548 A/C) polymorphisms. These polymorphisms were explored in 237 patients with HBV infection and in 237 individuals with HBV spontaneous clearance using a real-time polymerase chain reaction (RT-PCR) in a Turkish population. provided their written informed consent concerning the use of their blood specimen for this research. The work was carried out in accordance with th...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Evaluation of Forkhead Box P3 gene polymorphisms in chronic HBV infection

Akgöllü

2020

The Journal of Gene Medicine

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“…It is currently not known whether these effects are related to calcineurin‐dependent mechanisms, but the similarities between cyclosporin and tacrolimus, which have a completely different molecular structure and intracellular binding site, but a similar nephrotoxicity profile, suggest that this may be the case. Current data show that the tacrolimus‐induced acute nephrotoxicity in renal transplant patients may be associated with the FOXP3 rs3761548 variant . In this study, authors concluded that patients with FOXP3 rs3761548 A allele carriers are more likely to experience tacrolimus‐induced acute nephrotoxicity.…”

Section: Introductionmentioning

confidence: 65%

“…FOXP3 polymorphisms may be related to the outcomes of kidney transplantation and previous studies have shown that tacrolimus can target Tregs and inhibit them dose‐dependently and significantly . Previous studies have demonstrated, in KTRs, that the level of CD4+CD25+FOXP3+Tregs was lower in rejection groups compared to stable patients; meanwhile, the number of Tregs was positively correlated with the estimated glomerular filtration rate . Thus, these observations can be explained, at least partially, by an interaction between the FOXP3 rs3761548 variant and tacrolimus nephrotoxicity.…”

Section: Introductionmentioning

confidence: 96%

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Bentata

2019

Artificial Organs

100

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Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regi mens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower in cidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibil ity factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT. K E Y W O R D Sacute,

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“…A previous study also did not find association of both FOXP3 variant with acute or chronic rejection, even in a 10-years follow-up period ( Park et al, 2017 ). On the other hand, other studies reported association of the FOXP3 c.-23+2882A>C (A allele) polymorphism with long-term (2 and 5 years) acute rejection or nephrotoxicity in kidney recipients from different populations treated with cyclosporine- or TAC- based immunosuppressive therapy ( Qiu et al, 2012 ; Misra et al, 2016 ; Wu et al, 2017 ). The c.-23+2882A allele was also associated with worst graft survival and higher rate of recurrence of the original glomerular disease in kidney recipients at 3-year post-transplant ( Adamek et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients

et al. 2018

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Monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in blood levels of immunosuppressive drugs and adverse effects, but influence of pharmacodynamics-related genes remains to be elucidated. The influence of polymorphisms in genes of the mTOR and calcineurin signaling pathways on long-term clinical outcomes was investigated in Brazilian kidney transplant recipients within the 1-year post-transplant. Two-hundred and sixty-nine kidney transplant recipients were enrolled at a kidney transplant center in São Paulo city, Brazil, and treated with tacrolimus plus everolimus or mycophenolate sodium (clinical trial NCT01354301). Clinical and laboratory data, including renal function parameters and drug blood levels were recorded. Genomic DNA was extracted from blood samples. Polymorphisms in MTOR rs1057079 (c.4731G>A), rs1135172 (c.1437T>C), and rs1064261 (c.2997C>T); PPP3CA rs3730251 (c.249G>A); FKBP1A rs6033557 (n.259+24936T>C); FKBP2 rs2159370 (c.-2110G>T); and FOXP3 rs3761548 (c.-23+2882A>C) and rs2232365 (c.-22-902A>G) were analyzed by real-time PCR. Frequencies of gene polymorphisms did not differ among the treatment groups. Analysis of primary outcomes showed that patients carrying MTOR c.1437CC and FOXP3 c.-23+2882CC genotypes had higher serum creatinine than non-carriers (p < 0.05) at 1-year post-transplant. MTOR c.4731G allele (AG+GG genotype) was associated with increased risk for acute rejection (OR = 3.53, 95% CI = 1.09–11.48, p = 0.037). Moreover, 1-year cumulative incidence of rejection was higher in MTOR c.4731G allele carriers compared to AA genotype carriers (p = 0.027). Individually, analysis of secondary outcomes revealed that FKBP2 c.-2110GG genotype carriers had higher risk of leukopenia, FKBP1A n.259+24936C allele carriers had increased risk of constipation, and FOXP3 c.-22-902A or c.-23+2882A allele had higher risk of gastrointestinal disorders (p < 0.05). However, these results were not maintained in the multivariable analysis after p-value adjustment. In conclusion, variants in genes of mTOR and calcineurin pathways are associated with long-term impaired renal function, increased risk of acute rejection, and, individually, with adverse events in Brazilian kidney transplant recipients.

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

Abstract: 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.

Cited by 22 publications

References 47 publications

Evaluation of Forkhead Box P3 gene polymorphisms in chronic HBV infection

Evaluation of Forkhead Box P3 gene polymorphisms in chronic HBV infection

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients

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