Association Of SUMO4 Rs237025 Polymorphisms With Tacrolimus Elimation And New-onset Diabetes Mellitus After Liver Tansplantation

Tacrolimus metabolism and complications after liver transplantation have a negative effect on patient survival.SUMO4 rs237025 genetic variant can lead to a significant reduction of sumoylation capacity and higher NF-?B transcriptional activity.Activation of NF-?B suppressed the expression of CYP3 A gene,which can influence the metabolism of tacrolimus.In addition,NF-?B is a proinflammatory master switch that controls the production of a host of inflammatory markers and mediators,including interleukin-1,C-reactive protein,interleukin-6 and tumor necrosis factor-a.These could contribute significantly to the development of pancreatic ?-cell dysfunction,insulin resistance and diabetes.This study will investigate the association of SUMO4 rs237025 polymorphisms with tacrolimus elimation and new-onset diabetes mellitus after liver tansplantation.Part ? Association of SUMO4 rs237025 polymorphisms withtacrolimus elimination in the early period after liver transplantation Background and Aims: Individualized tacrolimus treatment can improve drug safety and efficacy.This study aimed to investigate the effect of donor and recipient small ubiquitin-like modifier 4(SUMO4)rs237025 polymorphisms on tacrolimus elimination after liver transplantation.Methods: A total of 297 patients(219 males and 78 females)who underwent orthotopic liver transplantation between January 2012 and December 2016 at Shanghai Jiao Tong University Affiliated Shanghai General Hospital,the First Affiliated Hospital of Zhengzhou University,and the First Affiliated Hospital of Zhejiang University were enrolled.We excluded patients with multiorgan transplantation,less than 1 month follow-up time and incomplete patient data.Genomic DNA was extracted from the donor and recipient liver tissue,CYP3A5rs776746 and SUMO4 rs237025 were genotyped.Results: Tac C/D ratios was significantly lower for donor SUMO4 rs237025 AA carriers than AG/GG carriers at weeks 1,2,3.In multivariate analysis,donor and recipient CYP3A5 rs776746,donor SUMO4 rs237025 and total bilirubin were independent predictors of Tac C/D ratios in the early post-transplantation period both in Cohort A and Cohort B.When combined donor CYP3A5 rs776746 and donor SUMO4 rs237025 genotypes,Tac C/D ratios was highly significant at all investigated time points within the four groups(Group 1 < Group 2 < Group 3 < Group 4,P <0.001,< 0.001,< 0.001,0.001).Conclusions: Donor SUMO4 rs237025 genetic variant was associated with higher Tac C/D ratios in the early period after LT.Combined donor CYP3A5 rs776746 and donor SUMO4 rs237025 genotypes could improve the predictive ability of Tac C/D ratios.Part ? SUMO4 rs237025 polymorphisms affects tacrolimuselimination via NF-?B signal pathway Background and Aims: Donor SUMO4 rs237025 polymorphisms can affect tacrolimus elimination in the early period time after liver transplantation,we aimed to investigate the potential mechanism.Methods: The activity of nuclear factor-?B(NF-?B)was evaluated by luciferase assay.The expressions of CYP3A5 were detected by qRT-PCR and western blotting.Results: CYP3A5 mRNA expression in liver tissues was significantly higher for SUMO4 rs 237025 AA carriers than AG/GG patients under inflammatory stimuli after liver transplantation(LT).Furthermore,we demonstrated that SUMO4 rs237025 G allele could increase NF-?B transcriptional activity under inflammatory condition.And activation of NF-?B suppressed the expression of pregnane X receptor(PXR)-mediated CYP3A5 gene.Conclusions: SUMO4 rs237025 G allele could increase NF-?B transcriptional activity under inflammatory condition,and activation of NF-?B suppressed theexpression of pregnane X receptor(PXR)-mediated CYP3A5 gene.Part ? Association of SUMO4 rs237025 polymorphisms withnew-onset diabetes milltus after liver transplantation Background and Aims: New-onset diabetes mellitus(NODM)is a common complication after liver transplantation(LT).The small ubiquitin-like modifier 4(SUMO4)rs237025 polymorphism has been reported to be associated with type 2diabetes mellitus(T2DM).This study aimed to evaluate the effect of donor and recipient SUMO4 rs237025 polymorphisms on NODM and the long-term consequences of NODM after liver transplantation.Methods: A total of 126 patients(102 males and 24 females)who underwent orthotopic liver transplantation between July 2007 and July 2014 at Shanghai Jiao Tong University Affiliated Shanghai General Hospital were enrolled.We excluded patients with multiorgan transplantation,a known history of diabates,less than 6month follow-up time and incomplete patient data.Genomic DNA was extracted from the donor and recipient liver tissue,SUMO4 rs237025 was genotyped.Results: Both donor and recipient SUMO4 rs237025 polymorphisms were found to be significantly associated with NODM after LT.In multivariate analysis,recipient age >50 years,tacrolimus trough concentrations >10 ng/mL at 1 month after LT,donor and recipient SUMO4 rs237025 genetic variant,and the combined donor and recipient SUMO4 rs237025 genetic variant were independent predictive factors of NODM.AUROC analysis indicated the higher predictive ability of the model containing combined donor and recipient SUMO4 rs237025 polymorphisms than the clinical model(p=0.046).Furthermore,Kaplan-Meier survival analysis demonstrated that NODM was related to significantly poorer patient survival in comparison with non-NODM patients(p=0.041).Conclusions: Both donor and recipient SUMO4 rs237025 polymorphisms contribute to the development of NODM after LT and NODM is a frequent complication that negatively affects patient survival.