Donor and recipient polymorphisms of MAPK signaling pathway genes influence post-transplant liver function in Chinese liver transplant patients taking tacrolimus
Introduction
Tacrolimus (TAC) is the most commonly used calcineurin inhibitors (CNIs) after liver transplantation to achieve adequate immunosuppression and to prevent acute rejection episodes. TAC is characterized by a narrow therapeutic index and high intra- and inter-individual variability in the pharmacokinetics (PK), which puts patients at risk of underexposure and allograft rejection or overexposure and toxicity (Venkataramanan et al., 1995, Watt and Charlton, 2010, Charlton et al., 2018, Defrancq et al., 2019, Prytuła and van Gelder, 2019). Therapeutic drug monitoring (TDM) is recommended to individualized TAC dosing(Brunet et al., 2019). However, it has been found that the TAC trough concentrations (C0) are only marginally associated with clinical outcomes. Some patients still experience acute rejection episodes or postoperative complications whereas their TAC blood concentrations are within the recommended therapeutic range(Masuda et al., 2006, Lemaitre et al., 2015). Currently, genetic polymorphisms relating to the PK and pharmacodynamics (PD) of TAC have received attention as potential mediators of the inter-individual differences in CNI concentrations and effects(Vafadari et al., 2013, Palanisamy et al., 2014). In particular, pharmacogenomic (PG) approaches that focus on the PD mechanisms of drugs have the potential to improve the therapeutic efficacy and safety(Salgado et al., 2017). However, the effects of genetic variants related to these mechanisms on clinical outcomes have been poorly explored.
TAC has two distinct mechanisms to exert its immunosuppressive effects. One is the inhibition of the protein phosphatase activity of calcineurin (CaN), leading to the blockade of the dephosphorylation and nuclear transport of nuclear factor of activated T-cells (NFAT) transcription factors(Bowman and Brennan, 2008). We have previously studied the potential impact of 77 single-nucleotide polymorphisms (SNPs) of FK506-binding protein (FKBP)1A, FKBP1B, PPP3CB, PPP3R1, NFATC1, and NFATC2 genes in the FKBP-CaN-NFAT signaling pathway on the efficacy and safety of TAC in Chinese renal transplant recipients(Wu et al., 2019).
The other is the inhibition of phosphorylation of the mitogen-activated protein kinase (MAPK) pathway, which is a signaling cascade involved in a wide variety of processes, particularly within immune system cells(Jeffrey et al., 2007). Activation of MAPKs is mediated by a three-tiered kinase module comprised of MAPK kinase kinases (MAP3Ks), MAPK kinases (MAP2Ks) and MAPKs through sequential protein phosphorylation(Huang et al., 2009). There are three distinct MAPK subgroups: the extracellular-signal-regulated kinases (ERK), the c-Jun N-terminal or stress-activated protein kinases (JNK) and p38(Fang and Richardson, 2005). TAC has been shown to inhibit the JNK and p38 pathways and is thought to inhibit the pathways upstream of the MAP3K level (Matsuda et al., 2000). JNK and p38 are activated through the MAPK signaling cascade by T cell and CD28 co-stimulatory receptors(Matsuda et al., 1998), and upon activation, translocate to the nucleus where they can fulfill their various roles(Aplin et al., 2002). This includes the regulating the activity of AP-1 members(Karin, 1995), which are involved in promoting the transcription of interleukin-2 (IL-2)(Macián et al., 2000) and other cytokines(Foletta et al., 1998). Indeed, the blockade of the p38 and JNK pathways was shown to prevent the expression of the IL-2 gene(Matsuda et al., 1998). The gene variations associated with these pathways may cause changes in the efficacy of TAC.
TAC is thought to inhibit the pathways upstream of the MAP3K level, as TAC has been seen to inhibit the activation of an MAPKK-K known as MAP3K1(Matsuda et al., 2000). Therefore, we speculate that the polymorphisms of MAP3K genes may influence the efficacy of TAC, which has not been explored so far. Therefore, the objective of this study was to investigate the effect of genetic polymorphisms of MAP3K genes on clinical events in Chinese liver transplant patients taking TAC-based immunosuppressive regimen.
Section snippets
Study population
Adult Chinese Han patients who were undergone liver transplantation and received TAC as their primary immunosuppressant in Huashan Hospital, Fudan University between February 2018 and September 2020 were included in this study. The exclusion criteria were as follows: (1) multiorgan transplant recipients; (2) recipients followed up for < 1 month as of the day when the medical record data is exported (September 20, 2022); (3) recipients without detailed information during follow-up period.
For
Clinical characteristics
A total of 175 liver transplant patients (27 females and 148 males) receiving TAC were enrolled in this study. The demographic and clinical characteristics of the study population are summarized in Table 1. Acute rejection and TAC-induced acute nephrotoxicity occurred between 3 and 459 days and 8 to 179 days after the transplantation, with incidence rates of 25.14 % (n = 44) and 21.14 % (n = 37), respectively. Whether to conduct induction therapy after transplantation was the only
Discussion
Pharmacogenetic approaches that focus on the pharmacodynamic mechanisms of drugs have the potential to increase the therapeutic efficacy and safety(Zdanowicz, 2010). Several studies have evaluated the effects of the PPP3CA(Salgado et al., 2017), FK506-binding protein (FKBP)-CaN-NFAT signaling pathway(Wu et al., 2019) and FOXP3(Wu et al., 2017) polymorphisms on the efficacy and toxicity of TAC in renal transplantation. However, the impact of genetic variants related to the mechanisms of TAC on
Funding information
This work was supported by the Shanghai “Rising Stars of Medical Talent” Youth Development Clinical Pharmacist Program (No.2018–1), Shanghai Science and Technology Innovation Program 2019 Key project in soft Science research field (No.19692107000), and the 2019 Key Clinical Program of Clinical Pharmacy (No. shslczdzk06502).
CRediT authorship contribution statement
Wanjie Niu: Data curation, Formal analysis, Visualization, Writing – original draft. Xinyi Zheng: Visualization, Validation. Ziran Li: Visualization, Validation. Zhuo Wu: Writing – review & editing. Mingkang Zhong: Supervision. Xiaoyan Qiu: Conceptualization, Methodology, Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors acknowledge all the doctors and nursing staff in our liver transplant department, without whom this work would not have been possible. In particular Professor Zhengxin Wang and Doctor Ruidong Li.
No writing assistance was utilized in the production of this manuscript.
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