Mycophenolic acid response biomarkers: A cell line model system-based genome-wide screen (original) (raw)
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Brazilian Journal of Pharmaceutical Sciences, 2022
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.
Mycophenolic acid pharmacogenomics in kidney transplantation
Journal of Translational Genetics and Genomics, 2020
Mycophenolic acid (MPA) is a potent antiproliferative drug prescribed to prevent acute rejection in kidney transplantation. MPA reversibly inhibits the enzymes involved in the synthesis of guanosine nucleotides, thus preventing DNA replication of immune cells. Consequently, the repression of both cell and humoral immunity induces renal allograft tolerance. MPA is an effective and safe immunosuppressive drug, but some patients show variability in drug concentration, acute rejection, graft dysfunction, or MPA-related adverse events. Although the pharmacogenomics of immunosuppressive drugs has been widely investigated, MPA has been explored to a lesser extent. This review of MPA pharmacogenomic studies, included pharmacokinetics, adverse events, and main clinical outcomes of MPA treatment in kidney transplantation. Associations of variants in genes encoding MPA metabolizing enzymes, transporters, and targets with drug efficacy and safety are described. Most pharmacogenetic studies have focused on small sample sizes and few simultaneously analyzed genetic variants. Some studies reported significant associations of pharmacokinetics-and pharmacodynamics-related genes with MPA exposure, acute rejection, graft dysfunction, hematological events, and gastrointestinal complications. However, even large cohorts did not replicate the findings, possibly due to divergent study design, immunosuppressive scheme, follow-up time, and other factors. Finally, the heterogeneity of aspects between studies limit conclusions on pharmacogenetic biomarkers of MPA in kidney transplantation.
Pharmacogenomics Journal, 2010
Mycophenolic acid (MPA) is a selective inhibitor of inosine 5 0 -monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 mmol l -1 ) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 mmol l -1 and 25 mmol l -1 . We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism.
Insights into pharmacogenomics and its impact upon immunosuppressive therapy
Transplant Immunology, 2002
The advent of the genomic era has brought about several new fields of study, one of them being pharmacogenomics, which seeks to link drug treatment (pharmaco-) with the individual's genetic make-up (genomics). Pharmacogenomics holds many promises for improved treatment of a large variety of medical conditions, including immunosuppression for organ transplantation and autoimmune disease. Many of these promises have, however, not yet been fulfilled. In this brief overview of the subject, we attempt to provide insights into the evolving field of pharmacogenomics and discuss some of its potential benefits and promises, technological tools used by pharmacogenomics, the reasons for delays in breakthroughs in the field, and the relevance of pharmacogenomics to immunosuppression. ᮊ
Clinical Pharmacology & Therapeutics, 2009
mycophenolate mofetil (mmF) is an immunosuppressive drug commonly used in the context of kidney transplantation. exposure to the active metabolite mycophenolic acid (mpa) is associated with risk of allograft rejection. mpa pharmacokinetics varies between individuals, the potential cause being the presence of genetic polymorphisms in key enzymes. We genotyped 338 kidney transplant patients for UGT1A8, UGT1A9, UGT2B7, and MRP2 polymorphisms and recorded mpa exposure and biopsy-proven acute rejections (Bpars) during a 1-year follow-up. Tacrolimus-treated patients who were UGT1A9 -275T>a and/or -2152C>T carriers displayed a 20% lower mpa area under the concentration-time curve from 0 to 12 h (auC 0-12 ) (P = 0.012). UGT1A9*3 carriers displayed a 49% higher mpa auC 0-12 when treated with tacrolimus and a 54% higher mpa auC 0-12 when treated with cyclosporine (P < 0.005). Cyclosporine-treated UGT1A8*2/*2 (518gg) patients had an 18% higher mpa auC 0-12 compared with noncarriers. Carrying the UGT1A9 -275T>a and/or -2152C>T polymorphism significantly predicted acute rejection in fixed-dose (FD) mmF-treated patients receiving tacrolimus (odds ratio 13.3, 95% confidence interval 1.1-162.3; P < 0.05). UGT1A9 -275T>a and/or -2152C>T genotyping may identify patients at risk of mpa underexposure and acute rejection when receiving treatment with mmF and tacrolimus.
Biomedicines
Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5′-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography–mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no ass...
Transplantation, 2019
Background: The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects such as nephrotoxicity, anemia, leukopenia and new onset diabetes after transplant (NODAT). In this report, we attempted to identify genetic variants which are associated with these adverse outcomes. Methods: We performed a genome-wide association study (GWAS), using a genotyping array tailored specifically for transplantation outcomes containing 722,147 SNPs, and two cohorts of kidney allograft recipients, a discovery cohort and a confirmation cohort, to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes. Results: Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified. Discussion: These results show that adverse effects associated with tacrolimus and mycophenolate are complex and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors. Oetting et al.
Proceedings of the National Academy of Sciences, 2010
Pharmacogenomics has employed candidate gene studies and, more recently, genome-wide association studies (GWAS) in efforts to identify loci associated with drug response and/or toxicity. The advantage of GWAS is the simultaneous, unbiased testing of millions of SNPs; the challenge is that functional information is absent for the vast majority of loci that are implicated. In the present study, we systematically evaluated SNPs associated with chemotherapeutic agent-induced cytotoxicity for six different anticancer agents and evaluated whether these SNPs were disproportionately likely to be within a functional class such as coding (consisting of missense, nonsense, or frameshift polymorphisms), noncoding (such as 3′UTRs or splice sites), or expression quantitative trait loci (eQTLs; indicating that a SNP genotype is associated with the transcript abundance level of a gene). We found that the chemotherapeutic drug susceptibility-associated SNPs are more likely to be eQTLs, and, in fact, more likely to be associated with the transcriptional expression level of multiple genes (n ≥ 10) as potential master regulators, than a random set of SNPs in the genome, conditional on minor allele frequency. Furthermore, we observed that this enrichment compared with random expectation is not present for other traditionally important coding and noncoding SNP functional categories. This research therefore has significant implications as a general approach for the identification of genetic predictors of drug response and provides important insights into the likely function of SNPs identified in GWAS analysis of pharmacologic studies.