Pharmacogenomics of mycophenolic acid in kidney transplantation: Contribution of immune response-related genesAbstract
Mycophenolic acid (MPA) inhibits IMPDH, involved in the guanosine nucleotides synthesis, and prevents DNA replication in immune cells. The repression of cell and humoral immunity by MPA induces allograft tolerance preventing acute rejection in solid organ transplantation. MPA is an effective and safe drug, but genetic and non-genetic factors have been implicated in the interindividual variability of drug response. Several studies have shown the impact of variants of pharmacokinetics or pharmacodynamics-related genes on MPA response in kidney transplantation. This review explored further the influence of genes involved in the immune response on clinical outcomes of kidney recipients on short- or long-term MPA treatment. Variants in genes related to T cell activation (CD28, CTL4, ICOS, PDPC1), pro-inflammatory cytokines (IL2, IL6, IL12A, IL12B, TNF, IFNG), immunomodulatory cytokines (IL4, IL10, TGFB1), and innate immune response (CD14, TLR2, TLR4) were shown to be associated with increased risk of acute rejection, graft function or survival, chronic graft nephropathy, viral infections or MPA-induced myelotoxicity. Some of the significant pharmacogenetic associations were confirmed by meta-analyses of kidney transplantation. These findings are suggestive that variants in immune response-related genes contribute to the variability of MPA response, and have potential application as biomarkers of acute rejection in kidney transplantation.
Keywords:
Immunosuppressive therapy; Mycophenolic acid; Kidney transplantation; Pharmacogenomics; Immune response
INTRODUCTION
Mycophenolic acid (MPA) is a potent antiproliferative drug prescribed broadly to prevent acute rejection in kidney transplantation. MPA is a reversible inhibitor of the inosine-5´-monophosphate dehydrogenase (IMPDH), an important enzyme involved in the de novo synthesis of guanosine nucleotides, which are essential for the proliferation of T and B cells (Bentata, 2020). Consequently, the depletion of the guanosine nucleotides by MPA prevents DNA replication and leads to repression of both cell and humoral-mediated immunity and induces tolerance to allograft in kidney transplantation (Staatz, Tett, 2014; Bentata, 2020; Da Silva et al., 2017). MPA also reduces the recruitment and infiltration of lymphocytes and other cells into a transplanted organ, therefore reducing the inflammatory response and preventing organ rejection (Staatz, Tett, 2014). MPA is considered a safe drug but some adverse events can occur, such as gastrointestinal complications, myelotoxicity, susceptibility to infections and neoplasms (Staatz, Tett, 2014; Bentata, 2020).
Mycophenolate mofetil (MMF) and enteric- coated mycophenolate sodium salt (EC-MPS) are the prodrug forms of MPA. MPA is metabolized by UDP-glucuronosyltransferases (UGT) into MPA phenyl (MPAG, inactive) and acyl (AcMPAG, active) glucuronides, which are eliminated mainly in the urine (Kiang, Ensom, 2018; Ferreira et al., 2020). Genetic and non-genetic factors influence the pharmacokinetics and pharmacodynamics of MPA, and it has been suggested to monitor MPA plasma levels to reduce the interindividual variability of its immunosuppressive response (Kiang, Ensom, 2018; Ferreira et al., 2020).
The contribution of pharmacogenomics in the response to immunosuppressive drugs has been widely investigated. Several clinical studies have reported the influence of gene polymorphisms on the efficacy and safety of MPA suggesting their potential contribution in the management of transplant patients. Most of these studies approached the influence of pharmacokinetics and pharmacodynamics- related genes on MPA response in different populations (Zaza et al., 2015; Genvigir et al., 2017; Guo et al., 2018; Li et al., 2018; Genvigir et al., 2020).
Mediators of the immune response, such as co- stimulatory molecules, cytokines and receptors, innate immune system and others, have been proposed to play important roles in immunologic tolerance of organ solid transplantation. Polymorphisms in genes involved in the immune response have been proposed as predictive factors of clinical graft outcomes in kidney transplantation (Stojanova, Pouché, Picard, 2016). This review explored the pharmacogenomic studies focused on immune response-related genes in kidney transplantation and the main clinical outcomes.
GENES RELATED TO T CELL ACTIVATION
T cell-mediated immune response plays an important role in immunological tolerance and allograft survival (Da Silva et al., 2017). T cell activation is modulated by co-stimulatory molecules, including CD28 and inducible costimulatory (ICOS), as well as by negative regulators, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PDCD1, PD-1). Variants in genes encoding these molecules were proposed to contribute to acute rejection and other allograft outcomes (Stojanova, Pouché, Picard, 2016).
A previous excellent review explored genetic polymorphisms in the immune response, and discussed their correlation with delayed graft function (DGF), acute rejection (AR), chronic graft nephropathy, graft survival and other clinical outcomes in kidney transplantation (Stojanova, Pouché, Picard, 2016).
CD28, ICOS, CTLA4 and PDCD1 are the most studied genes involved in T cell activation (Figure 1), and the studies that reported significant influence on MPA-related clinical outcomes in kidney transplantation are shown in Table I.
Schematic representation of immune response-related genes involved in kidney transplantation.
CD28 & ICOS
The CD28 rs3116496 (c.243+17T>C), an intronic variant also named 17T>C, was investigated in a cohort of adult kidney recipients on MMF therapy, and the 17C allele was associated with increased risk of AR (OR: 1.82, 95%CI: 1.13-2.94, p<0.05) but not with DGF or chronic graft nephropathy (Pawlik et al., 2014) (Table I). Other studies reported a lack of association of the CD28 17T>C with AR, graft function or graft survival in adult patients (Kusztal et al., 2010) (Niknam et al., 2017). In the same way, the CD28 upstream variant rs35593994 (c.- 594G>A) was not associated with AR, graft function or graft survival, in a large cohort of adult kidney recipients (Haimila et al., 2009) (Table II).
Two meta-analyses explored variants in genes of co-stimulatory molecules and found an association of the CD28 rs3116496 (C allele) with kidney allograft rejection (Han et al., 2014; Liu et al., 2017a). A recent systematic meta-analysis including data from previous meta-analyses and genome-wide association studies (GWAS) also reported CD28 rs3116496 association with AR in kidney recipients, but the epidemiology credibility (cumulative evidence) was weak (Cargnin et al., 2020).
Haimila et al. (2009) investigated the influence of six ICOS variants rs11883722 (c.-693G>A), rs10932029 (c.58+173T>C), rs10183087 (c.*2A>C), rs4404254 (c.*964T>C), rs10932037 (c.*1024C>T) and rs4675379 (c.*1773G>C) on kidney transplantation outcomes in a large cohort of adult patients on long-term MMF therapy. The c.*2A and c.*964T alleles were associated with (DGF) or graft non-function, whereas the c.*1024T allele was associated with low graft survival. However, all ICOS variants did not influence the AR outcome (Haimila et al., 2009) (Table I). Another study explored the ICOS 1720C>T variant, which was not related to AR, graft function or survival in kidney recipients on long-term MMF therapy (Niknam et al., 2017) (Table II).
CTLA4 & PDCD1
The CTLA4 rs231775 (c.49A>G, Thr17Ala) missense variant was associated with increased risk of AR in adult kidney recipients on MMF therapy (c.49G allele, OR: 5.5, 95%CI: 0.96-31.44, p<0.05) (Gendzekhadze et al., 2006), (OR: 1.72, 95%CI: 1.01-2.93) (Gao et al., 2012; Canossi et al., 2013) (Table I). On the other hand, c.49A>G was not associated with AR in small (Dmitrienko et al., 2005; Ruhi et al., 2015) (Niknam et al., 2017) and large cohorts of adult kidney recipients (Haimila et al., 2009; Kusztal et al., 2010) (Table II).
Upstream and intronic variants in CTLA4 were also investigated in various pharmacogenetic studies. Canossi et al. (2013) also explored the CTLA4 rs16840252 (c.-1147C>T), rs5742909 (c.-318C>T), rs3087243 (c.*1148+236G>A, also named CT60G>A) and rs11571319 G>A variants and found association of the CT60AA genotype and CCAA haplotype with increased risk of AR adult kidney recipients on MMF treatment. Likewise, Gao et al. (2012) assessed five variants in the CLTA4 and found an association of the rs733618 (c.-1722T>C) T allele and TACGG haplotype with AR in adult patients. Moreover, Ruhi et al. (2015) investigated four CLTA4 variants and the T allele of the rs5742909 (c.-318C>T) was associated with increased risk of AR OR: 3.45, 95%CI: 1.13-10.56, p<0.05). Conversely, the CTLA4 rs4553808 (c.-1661AA genotype) was reported to reduce the risk of AR in male kidney recipients (Niknam et al., 2017) (Table I).
Other studies reported lack of association of the CTLA4 c.-318C>T, c.-1147C>T, c.-1661A>G, c.-1722T>C, CT60G>A or rs11571319 (c.*144G>A) variants with AR in small (Dmitrienko et al., 2005; Gendzekhadze et al., 2006; Gao et al., 2012; Canossi et al., 2013; Ruhi et al., 2015; Niknam et al., 2017) and large cohorts (Haimila et al., 2009; Kusztal et al., 2010) of kidney recipients treated with MMF. The CTLA4 (AT)n L>H is a short tandem repeat (STR), which was also not related to AR in adult kidney recipients (Kusztal et al., 2010) (Table II).
The impact of CTLA4 variants on chronic rejection and graft function and survival was also explored in kidney recipients on MMF therapy. The c.49AA/LL haplotype was associated with long-term graft function, assessed by the estimated glomerular filtration rate (eGFR), in adult patients (Kusztal et al., 2010) (Table I). On the other hand, none of the CTLA4 variants c.49A>G, c.-318C>T, c.-1661A>G, c.-1722T>C, CT60G>A and STR (AT)n) L>H were associated with chronic rejection (Gendzekhadze et al., 2006), graft function, survival or failure, or patient death (Dmitrienko et al., 2005; Haimila et al., 2009; Kusztal et al., 2010; Niknam et al., 2017) (Table II).
Two studies explored the impact of CTLA4 variants on the incidence of viral infection in adult kidney recipients on MMF therapy. Guo et al. (2013) analyzed five variants and reported association of the c.-1661GG genotype (OR: 4.88, 95%CI: 1.70-13.67, p<0.05) and the haplotypes CGTAG and CGCAG with increased risk of viral infection, but not with bacterial infection. Misra et al. (2015) also explored the influence of seven polymorphisms on the incidence of cytomegalovirus (CMV) infection in adult patients. They found association of the variants c.49A>G (c.49GG, OR:2.46, 95%CI: 1.10- 5.52, p<0.05) and CT60G>A (CT60GG, OR: 2.78, 95%CI: 1.21-6.39, p<0.05), as well as the GCTTGG haplotype and STR (AT)n H allele were associated with symptomatic CMV infection. Moreover, c.49A>G and CT60G>A were also associated with reduced CMV disease-free survival in this cohort (Misra et al., 2015) (Table I).
Several meta-analyses explored the impact of CTLA4 variants on AR and other outcomes in kidney transplantation. CTLA4 rs231775 (c.49A>G) was found to increase the risk of AR, DGF or overall survival, suggesting its involvement in the susceptibility to AR or DGF in kidney recipients (Duan et al., 2012; Misra et al., 2014; Gao et al., 2015; Liu et al., 2017a; Yang et al., 2017b). CTLA4 rs733618 (c.-1722T>C), rs3087243 (CT60G>A) and STR (AT)n L>H (AT)n variants were also associated with AR or DGF, whereas the c.-318C>T and other upstream variants showed no impact on AR and other outcomes (Duan et al., 2012; Han et al., 2014; Misra et al., 2014; Liu et al., 2017a; Yang et al., 2017a). Recently, a re-analysis of data from several meta-analyses and GWAS also reported the association of the CTLA4 c.49A>G and c.-1722T>C variants with AR in kidney recipients, but the cumulative evidence was weak (Cargnin et al., 2020).
The PDCD1 rs2227981 (c.804T>C, p.Ala268=) and rs11568821 (c.627+189G>A), synonymous and intronic variants respectively, were explored in kidney transplantation, but no association was found with AR, graft function or graft survival in a large cohort adult patients on MMF therapy (Haimila et al., 2009). Lack of association between these variants and AR and graft survival was also reported in kidney recipients on long- term MMF treatment (Niknam et al., 2017) (Table II). Interestingly the missense variant PDCD1 rs2227982 (c.644C>T, p.Ala215Val) increased the risk of AR in male adult patients (CT genotype, OR: 3.19, 95%CI: 0.92- 11.01, p<0.05) (Niknam et al., 2017) (Table I). Two meta- analyses investigated these PDCD1 variants as predictors of AR in kidney transplantation, but no association was found with allograft rejection suggesting that they are not conspicuous risk factors for developing AR (Han et al., 2014; Liu et al., 2017a).
The PDCD1 rs11568821 was associated with increased risk of CMV in seropositive patients (A allele, OR: 2.54, 95%CI: 1.25-5.15, p=0.010) (Hoffmann et al., 2010) (Table I). This finding was also reported in a recent systematic review that assessed variants in cytokine genes in kidney transplantation (Sakharkar, Deb, Mashayekhi, 2020).
GENES RELATED TO PRO-INFLAMMATORY CYTOKINES
Cytokines have an important role in the immune response by participating of the Th1 and Th2 responses after T cell activation. Th1 lymphocytes contribute to inflammation by secreting pro-inflammatory mediators, such as interleukin (IL) 2, IL-6, IL-12, tumor necrosis factor-alpha (TNFα) and interferon-gamma (IFNγ) (Figure 1), which are involved in cell-mediated immunity and allograft rejection (Stojanova, Pouché, Picard, 2016; Da Silva et al., 2017). On the other hand,, Th2 lymphocytes are immunomodulatory cells that facilitate allograft tolerance by secreting anti-inflammatory cytokines that regulate cellular and humoral responses and contribute to allograft protection (Stojanova, Pouché, Picard, 2016).
The IL-2 was initially characterized as a T cell growth factor and has a unique linking role between adaptive and innate immune response. During the early stage of immune response, the T cell activation induces the expression of IL-2, which promotes proliferation and differentiation of T and B cells. (Stojanova, Pouché, Picard, 2016; Da Silva et al., 2017; Bendickova, Fric, 2020).
The IL-6 is a pro-inflammatory pleiotropic cytokine and a mediator of the acute phase responses that regulates inflammatory events. It is involved in leukocyte trafficking, T-cell proliferation, B-cell differentiation and survival. It is produced by endothelial cells, fibroblasts, monocytes, and macrophages in response to different stimuli during systemic inflammation (Stojanova, Pouché, Picard, 2016). The IL-12 is a potent pro-inflammatory cytokine composed of the IL-12A (p35) and IL-12B (p40) subunits, which are encoded by IL12A and IL12B, respectively. IL- 12 is an essential inducer of Th1 cell response, as well as the activation and link the innate and acquired immune responses (Smith, Humphries, 2009).
The TNFα is produced by activated macrophages and T cells. It is involved in inflammation, activating endothelial cells, up-regulating cell adhesion molecules and participating in the recruitment of different leukocytes (Stojanova, Pouché, Picard, 2016).
The IFNγ is produced by Th1 lymphocytes and other adaptive and innate immune cells. It activates macrophages, increases the T cell activation, and induces cytotoxic activities and apoptosis (Stojanova, Pouché, Picard, 2016; Da silva et al., 2017).
Variants in genes encoding these pro-inflammatory cytokines have been proposed to impact acute rejection and other kidney transplant outcomes in patients treated with MPA and the significant results are shown in Table III.
IL2, IL6, IL12A & IL12B
Two variants in the IL2, rs2069762 (c.-385T>G, also known as -330T>G) and rs2069763 (c.114G>T, p.Leu38=) were explored in adult kidney recipients on MMF therapy. Satoh et al. (2007) reported association of the IL2 -330TT genotype with chronic allograft nephropathy (OR: 4.57, 95%CI: 1.04-20.11, p<0.05) in a small cohort of Japanese adult patients (Table III). The IL2 -330T>G and c.114G>T variants were also investigated as predictive markers of AR, but no association was found in adult kidney recipients from the open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] (Grinyó et al., 2008). In the same way, IL2 -330T>G was not related to AR in adult patients from the FDCC study (Chen et al., 2014), and in other cohorts on short-term MMF treatment (Cilião et al., 2017; Hu et al., 2020). Lack of association between the variant IL2 rs2069762 (-330T>G) and risk of acute renal graft rejection was confirmed in a meta-analysis of eight case-control studies (Hu et al., 2015) (Table IV).
The intronic variant IL6 rs1800795 (-174G>C) was investigated in kidney recipients on MMF therapy. An early study reported an association of the -174G allele with chronic graft nephropathy in a small cohort of adult patients (Viklický et al., 2004). Further, the -174G allele was found to increase the risk of AR (OR: 2.11, 95%CI: 1.00-4.44, p<0.05) in patients on short-term MMF treatment (Karimi et al., 2012) (Table III). On the other hand, this variant was not associated with AR or chronic rejection in other cohorts on long-term follow-up (Gendzekhadze et al., 2006; Dhaouadi et al., 2013; Gaafar et al., 2014) (Table IV). The IL6 rs1800795 was assessed by a meta-analysis, but no association of the -174G allele (high producer) was found with AR in kidney recipients (Lv et al., 2012).
A recent study explored the upstream variant IL6 the rs10499563 (-6331T>C) and found an association of the -6331CC genotype (OR: 6.6, 95%CI: 1.7-25.8, p<0.05) with AR within two weeks of kidney transplantation (Hu et al., 2020) (Table III).
Variants in the 3´UTR of IL12A rs568408 (c.*121G>A) and IL12B rs3212227 (c.*159T>C, also named as 1188A>C) were assessed in adult kidney recipients. In a large cohort of patients, the IL12A rs568408 A allele was associated with time to MMF- related anemia (HR: 1.98, 95%CI: 1.39-2.82, p<0.001), but not with leukopenia, (Jacobson et al., 2011) (Table III). The IL12A c.*121G>A was also investigated in patients from the Dominos Study on short-term enteric-coated mycophenolate sodium (EC-MPS) treatment, but this variant was not related to AR, leukopenia, anemia or diarrhea (Woillard et al., 2014) (Table IV).
The IL12B 1188A>C was associated with reduced risk of DGF (AA genotype, OR: 0.45, 95%CI: 0.21-0.96, p<0.05) (Table III), but this variant had no impact on AR or graft function in adult kidney recipients on MMF treatment (Perovic et al., 2018). Earlier studies, also reported a lack of association of the IL12B 1188A>C with AR, DGF, graft survival, or chronic graft nephropathy (Satoh et al., 2007; Hoffmann et al., 2009) (Table IV). Three studies explored the influence of IL12B rs3212227 on CMV infection in a large cohort and the C allele as associated with increased risk of CMV infection, including in seropositive adult patients (C allele, OR=1.91, 95%CI: 1.10-3.30, p=0.021) (Hoffmann et al., 2008; Hoffmann et al., 2009; Hoffmann et al., 2010) (Table III). This finding was also reported in a recent systematic review that assessed variants in cytokine genes in kidney transplantation (Sakharkar, Deb, Mashayekhi, 2020).
TNF
The TNF rs1800629 (c.-488G>A, also named -308G>A) is an upstream variant that was extensively explored in MPA-related pharmacogenomic studies. TNF -308A allele was associated with increased risk of AR in adult kidney recipients from the CAESAR study (OR: 2.18, 95% CI: 1.08-4.41, p<0.05) (Grinyó et al., 2008) and from a Spanish cohort (OR: 2.78, 95%CI: 1.40-5.51, p<0.05) (Sánchez-Fructuoso et al., 2016) on MMF treatment (Table III). Other studies reported no impact of the TNF -308G>A on AR in adult patients from different cohorts on short-term (Azarpira et al., 2009; Cilião et al., 2017; Hu et al., 2020) or long-term on MMF therapy (Weimer et al., 2003; Dmitrienko et al., 2005). (Gendzekhadze et al., 2006; Dhaouadi et al., 2013; Gaafar et al., 2014; Perovic et al., 2018) (Table IV). Interestingly, the TNF*H/TGFB1*H/IL10*H haplotype, which includes the TNF -308A allele (H*), was associated with increased risk of AR (OR: 15.75. 95%CI: 0.98-528.85, p<0.05) and reduced graft survival in adult patients on long-term MMF therapy (Dhaouadi et al., 2013).
An earlier meta-analysis of 28 studies reported that TNF -308G>A increased the risk of AR (GG genotype, OR: 1.39, 95%CI: 1.06-1.82, p=0.02) in kidney recipients (Hu et al., 2011). A recent meta- analysis of 33 studies, including previous meta-analyses and GWAS, found TGF -308GG genotype associated with AR (OR: 1.41, 95%CI: 1.05-1.88, p=0.022) in kidney recipients, but the cumulative evidence was weak (Cargnin et al., 2020).
TNF -308G>A was associated with reduced risk of chronic rejection (-308A allele, OR: 0.1, 95%CI: 0.005-1.64, p<0.05) in a small cohort of adult kidney recipients (Gendzekhadze et al., 2006) (Table III). On the other hand, this variant did not increase the risk of chronic graft nephropathy (Satoh et al., 2007) chronic rejection (Dhaouadi et al., 2013), DGF or graft function (Perovic et al., 2018), and graft failure or patient death (Dmitrienko et al., 2005) in adult kidney recipients (Table IV). A recent study found TNF -308G allele carriers had low eGFR, but not with IL-6 and IL-10 plasma levels, in adult patients on long-term MMF therapy (Alves et al., 2020). The variant TNF rs361525 (c.-418G>A, also named -238G>A) was also investigated in a small cohort of kidney recipients, but no impact was found on chronic graft nephropathy (Satoh et al., 2007) (Table IV).
Grenda et al. (2009) reported association of the TNF -308G allele with leukopenia, an MFF-induced myelotoxicity, in a cohort of pediatric kidney recipients on one-year MMF treatment (Table III). The influence of TNF -308G>A on CMV infection was also explored, but no association was found in Hispanic adult patients on long-term MMF or EC-MPS treatment (Vu et al., 2014b) (Table IV).
IFNG
The impact of the IFNG rs2430561, an intronic variant (c.115-483A>T, also named 874T>A), on clinical outcomes of kidney transplantation was also largely investigated. The IFNG 874T allele was associated with increased risk of AR (OR: 2.08, 95%CI: 1.12-3.88, p<0.05) in adult patients on short-term MMF therapy (Karimi et al., 2012). Conversely, the IFNG 874TT genotype was associated with reduced risk of AR (OR: 0.40, 95%CI: 0.19-0.85, p<0.05) and high graft survival time in adult kidney recipients on long-term treatment (Vu et al., 2014a) (Table III). Other studies did not find an influence of the IFNG 874T>A on AR in small (Gendzekhadze et al., 2006; Azarpira et al., 2009; Gaafar et al., 2014; Perovic et al., 2018) and larger (Singh et al., 2009; Dhaouadi et al., 2013; Vu et al., 2014b) cohorts of adult kidney recipients on MMF treatment (Table IV).
A meta-analysis of 13 case-control studies reported that carriers of the IFNG 874T allele (AT+TT genotypes) had an increased risk of AR (OR: 1.36, 95%CI: 1.07- 1.73, p<0.05) in kidney recipients (Ge et al., 2013). Similar results were found in two recent meta-analyses, which suggested the IFNG 874T>A as a relevant clinical biomarker for acute rejection in kidney transplantation (Cargnin et al., 2020; Eiamsitrakoon et al., 2020).
The IFNG 874T>A was also not associated with chronic rejection, chronic graft nephropathy or DGF and graft function in patients treated with MMF (Gendzekhadze et al., 2006; Satoh et al., 2007) (Dhaouadi et al., 2013; Perovic et al., 2018) (Table IV). Lack of association between IFNG 874T>A and chronic rejection in kidney transplantation was also reported in a recent meta-analysis (Eiamsitrakoon et al., 2020).
An early study also investigated an IFNG STR (126- 134 bp) but no association was found with AR, graft failure or patient death (Dmitrienko et al., 2005). Other variants, such as rs2069718, rs2870953 and rs12369470, also did not influence AR and graft survival (Vu et al., 2014a) (Table IV).
Three studies explored the impact of IFNG variants on susceptibility to viral infection in kidney recipients on MMF therapy. The IFNG rs2430561 (874A allele) was associated with increased risk of CMV infection (OR: 1.92, 95%CI: 1.18-3.11, p<0.05) and lower CMV infection-free survival (three-year follow- up) in adult patients on MMF or EC-MPS therapy (Vu et al., 2014b). Another study also investigated four variants in the IFNG (rs2430561, rs2069718, rs2870953, rs12369470) and found association of the rs2430561 (874TT genotype, OR: 0.72, 95%CI: 0.40-1.20) and AGT haplotype (OR: 0.43, 95% CI: 0.25-0.73) with reduced risk of BK polyomavirus (BKV) infection in adult patients (Vu et al., 2014a) (Table III). On the other hand, IFNG rs2430561 was not associated with the risk of CMV infection in a larger cohort of adult patients (Santiago et al., 2020) (Table IV). A recent systematic review assessed variants in cytokine genes in kidney transplantation and reported an association between the IFNG 874T>A variant and CMV infection (Sakharkar, Deb, Mashayekhi, 2020).
GENES RELATED TO IMMUNOMODULATORY CYTOKINES
Immunomodulatory cytokines secreted by Th2 lymphocytes, such as IL-4 and IL-10, and transforming- growth factor β1 (TGF-β1) (Figure 1), which regulate negatively the T and B cell-mediated immune response, play important roles in the allograft tolerance, predominantly through their ability to inhibit T cell activation (Stojanova, Pouché, Picard, 2016; Li et al., 2019). TGF-β1 is also involved in various biological processes related to cell growth, proliferation and differentiation, and fibrosis. Several studies investigated the influence of variants in IL4, IL10 and TGFB1 on MPA- related clinical outcomes in kidney transplantation with significant results shown in Table III.
IL4 & IL10
Two studies assessed the upstream variant IL4 rs2243250 (c.-589C>T, also named -590C>T) but no association was found with AR (Karimi et al., 2012) or chronic graft nephropathy in small cohorts of adult kidney recipients on MMF therapy (Satoh et al., 2007) (Table V). Lack of association between IL4 -590C> and AR was also found in a meta-analysis that assessed six studies on kidney transplantation (Wu et al., 2013).
Several studies investigated IL10 upstream variants rs1800896 (-1082A>G), rs1800871 (-819C>T) and rs1800872 (-592C>A) and rs1800894 (-851C>T) in MMF-treated kidney recipients (Table V). The -592C>A was the only variant associated with increased risk of AR (-592AA, OR: 4.71, 95% CI: 1.52-14.55, p<0.05) in adult patients from the CAESAR Study (Grinyó et al., 2008) (Table III).
Other works also explored the IL10 rs1800896, rs1800871 or rs1800872 variants but reported lack of association with AR in small (Weimer et al., 2003; Dmitrienko et al., 2005; Gendzekhadze et al., 2006; Azarpira et al., 2009; Gaafar et al., 2014; Perovic et al., 2018; Hu et al., 2020) and larger cohorts (Dhaouadi et al., 2013; Chen et al., 2014; Cilião et al., 2017) of adult patients. Likewise, IL10 rs1800896, rs1800871 or rs1800872, did not impact on DGF or graft function (Perovic et al., 2018), chronic rejection (Gendzekhadze et al., 2006; Dhaouadi et al., 2013), chronic graft nephropathy (Satoh et al., 2007), graft failure or patient death (Dmitrienko et al., 2005). IL10 rs1800896 and rs1800872 were also assessed in kidney recipients and no association was found with susceptibility to CMV infection in adult patients on long-term MMF or EC-MPS treatment (Vu et al., 2014b) (Table V).
An earlier meta-analysis assessed the impact of IL10 -1082G>A, -819C>T and -592C>A variants in kidney transplantation and found the haplotype A-C-C (low expression) are associated (OR: 1.3, 95%CI: 0.9-1.6, p=00.44) with poor outcomes, such as graft failure, chronic allograft nephropathy, AR or chronic graft rejection (Thakkinstian et al., 2008). Further meta-analyses showed that IL10 -1082G>A, -819C>T or 592C>A individual variants or haplotypes were not associated with increased risk of AR or chronic rejection (Xiong et al., 2015; Hu et al., 2016).
TGFB1
The TGFB1 missense variants rs1800470 (869T>C, p.Pro10Leu) and rs1800471 (915G>C, Arg25Pro) have been explored in kidney recipients on MMF therapy. Several studies reported a lack of association of either TGFB1 869T>C and 915G>C variant with AR in adult kidney recipients on short-term MMF therapy (Karimi et al., 2012; Cilião et al., 2017; Zheng et al., 2019). These variants were also not associated with AR in adult patients on long-term MMF therapy (Dmitrienko et al., 2005; Gendzekhadze et al., 2006; Dhaouadi et al., 2013; Gaafar et al., 2014), as well as from the CAESAR study (Grinyó et al., 2008) and FDCC study (Chen et al., 2014). The upstream variant rs1800469 (-509C>T) in the TGFB1 was also not related to AR in adult patients treated on two-week MMF treatment (Hu et al., 2020) (Table V).
Dmitrienko et al. (2005) found an association of the TGFB1 915G>C with increased risk of graft failure in adult kidney recipients on MMF therapy (Table III). On the other hand, the variants 869T>C, 915G>C or -509C>T variants had no impact on chronic rejection (Gendzekhadze et al., 2006), (Dhaouadi et al., 2013), chronic graft nephropathy (Satoh et al., 2007) or patient death (Dmitrienko et al., 2005) in adult patients (Table V).
Five meta-analyses explored the influence of TGFB1 missense variants (869T>C and 915G>C) on AR in kidney transplantation. In an earlier study, the TGFB1 869TC genotype carriers had increased risk (OR: 1.5, 95%CI: 1.0-2.2, p=0.34) of combined poor outcomes (AR, chronic graft rejection, graft failure or chronic allograft nephropathy) (Thakkinstian et al., 2008). Further, TGFB1 869CC genotype was associated with increased risk of AR in kidney donors (OR: 1.47, 95%CI: 1.05-2.06, p=0.025) but not in kidney recipients (p>0.05) (Ge et al., 2014b). Lack of association between TGFB1 +869T>C and +915G>C variants or haplotypes and AR susceptibility was also reported in other meta-analyses of kidney transplantation (Ge et al., 2014a; Li et al., 2019).
The TGFB1 869/915 TT/GG+TC/GG haplotype, classified as a high producer of TGF-β1 in vitro (Smith, Humphries, 2009), was associated with chronic graft nephropathy (OR: 3.6, 95%CI: 2.2-5.8, p<0.001), whereas the individual variants were not, in kidney recipients from eight studies (Liu et al., 2017b).
GENES RELATED TO INNATE IMMUNE RESPONSE
Proteins of the innate immune system, such as CD14 and Toll-Like Receptors (TLR), have an important role in pathogen recognition and activation of the innate immune response. TLR also can modulate T cell function and act as costimulatory receptors to enhance proliferation and/ or cytokine production of in activated T cells (Figure 1). TLR2, TLR4 and the related molecule CD14 have been proposed to initiate inflammation and tissue injury, which may affect graft function and survival in solid organ transplantation (Stojanova, Pouché, Picard, 2016). Some studies investigated the influence of variants in CD14, TLR2 and TLR4 on MPA-related clinical outcomes in kidney transplantation and Table III shows the significant results.
CD14
The intronic variant CD14 rs2569190 (c.-260C>T, also named -159 C>T) was explored in adult kidney recipients on long-term MMF therapy. Abdolvahabi et al. (2018) described the association of rs2569190 (-159TT genotype) with increased risk of AR (OR: 12.26, 95%CI: 4.02-37.31, p<0.05) and graft loss (OR: 8.75, 95%CI, 2.81-27.16, p<0.05) and reduced graft survival (Table III). Previous studies did not find an association of the CD14 rs2569190 with AR, DGF, chronic graft nephropathy or graft survival (Viklický et al., 2004; Krüger et al., 2010; Krichen et al., 2013). This variant did not also contribute to the incidence of CMV and other infections (Krüger et al., 2010; Krichen et al., 2013) (Table VI).
TLR2 & TLR4
Three studies investigated TLR2 variants in kidney recipients on MMF treatment. The missense variant TLR2 rs5743708 (c.2258G>A, Arg753Gln) did not contribute to AR, DGF, graft function and survival, or CMV and other infections in adult patients on long-term follow-up (Krüger et al., 2010; Abdolvahabi et al., 2018). Likewise, a lack of association was found between the synonymous variant TLR2 rs3804100 (c.1350T>C, Ser450S=) and AR in adult patients within the first two weeks of therapy (Hu et al., 2020) (Table VI).
The TLR4 missense variants rs4986790 (c.896A>G, p.Asp299Gly) and rs4986791 (c.1196C>T, p.Thr399Ile) were explored, but no association with AR was found in adult kidney recipients on long-term (Krüger et al., 2010; Krichen et al., 2013; Abdolvahabi et al., 2018) and short-term (Hu et al., 2020) MMF therapy. Both variants had also no impact on DGF, chronic graft nephropathy, graft function and survival, or CMV and other infections (Krüger et al., 2010; Krichen et al., 2013) (Table VI).
CONCLUSIONS
Variants in genes related to T cell activation (CD28, CTL4, ICOS, PDPC1), pro-inflammatory cytokines (IL2, IL6, IL12A, IL12B, TNF, IFNG), immunomodulatory cytokines (IL10, TGFB1), and innate immune response (CD14) are associated with increased risk of acute rejection, graft function or survival, chronic graft nephropathy, viral infections or MPA-induced myelotoxicity in kidney recipients. These findings are suggestive that variants in immune response-related genes contribute to the variability of MPA response, and have potential application as biomarkers of acute rejection in kidney transplantation.
ACKNOWLEDGMENTS
FDVG and TDCH were recipients of fellowships from FAPESP, Brazil. MHH and RDCH are recipients of fellowships from CNPq, Brazil.
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