An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid (original) (raw)
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Genetic Testing, 2008
Inosine monophosphate dehydrogenase type II (IMPDH2) is the target for immunosuppression by mycophenolic acid and has been linked to resistance of tumor cells to chemotherapy. Determining the frequency of IMPDH2 genetic polymorphisms can inform the design of clinical studies investigating the impact of IMPDH2 genetic variability on both cancer therapy and immunosuppression. Frequencies of three IMPDH2 polymorphisms (rs4974081, rs5848860, and rs11557540) in >400 DNA samples from four different racial=ethnic groups (Caucasian, African American, Hispanic, and Asian populations) were characterized by the pyrosequencing genotyping method. For rs5848860 1591 CTT=-(500 G=EG) and rs11557540 1345 A=G (418 D=G), we did not observe any variant alleles in all DNA samples from these populations, which suggests that these variants could simply be sequencing errors rather than real polymorphisms. The observed frequency of the 5 0-upstream singlenucleotide polymorphism (SNP) rs4974081 A=G was similar to that previously reported in the NCBI databank (dbSNP). An in silico functional analysis using FASTSNP predicts that this promoter SNP rs4974081 (-3624 A=G) could be a potential transcription factor binding site. This finding suggests that rs4974081 could be a good candidate SNP for association studies with immunosuppressive and chemotherapeutic therapy outcomes.
British Journal of Pharmacology, 2010
Inosine monophosphate dehydrogenases, encoded by IMPDH1 and IMPDH2, are targets for the important immunosuppressive drug, mycophenolic acid (MPA). Variation in MPA response may result, in part, from genetic variation in IMPDH1 and IMPDH2. EXPERIMENTAL APPROACH We resequenced IMPDH1 and IMPDH2 using DNA from 288 individuals from three ethnic groups and performed functional genomic studies of the sequence variants observed. KEY RESULTS We identified 73 single nucleotide polymorphisms (SNPs) in IMPDH1, 59 novel, and 25 SNPs, 24 novel, in IMPDH2. One novel IMPDH1 allozyme (Leu275) had 10.2% of the wild-type activity as a result of accelerated protein degradation. Decreased activity of the previously reported IMPDH2 Phe263 allozyme was primarily due to decreased protein quantity, also with accelerated degradation. These observations with regard to the functional implications of variant allozymes were supported by the IMPDH1 and IMPDH2 X-ray crystal structures. A novel IMPDH2 intron 1 SNP, G > C IVS1(93), was associated with decreased mRNA quantity, possibly because of altered transcription. CONCLUSIONS AND IMPLICATIONS These results provide insight into the nature and extent of sequence variation in the IMPDH1 and IMPDH2 genes. They also describe the influence of gene sequence variation that alters the encoded amino acids on IMPDH function and provide a foundation for future translational studies designed to correlate sequence variation in these genes with outcomes in patients treated with MPA.
Inter-ethnic variability of three functional polymorphisms affecting the IMPDH2 gene
Molecular Biology Reports
Human type II inosine monophosphate dehydrogenase (IMPDH2) is a key enzyme in the purine nucleotide biosynthetic pathway and constitutes a pivotal biological target for immunosuppressant and antiviral drugs. Several Single Nucleotide Polymorphisms (SNP) affecting the IMPDH2 gene sequence have been reported with potential functional relevance and could impact drugs response. We aimed to determine the frequency of three of these polymorphisms, namely g.3375C>T (Leu263Phe), c.-95T>G and IVS7+10T>C, in Caucasians, Tunisians, Peruvians and Black Africans (Gabonese and Senegalese). The g.3375C>T and c.-95T>G polymorphisms are rare with a Minor Allele Frequency ≤1.0% in our populations, whereas the third variant, IVS7+10T>C, is more frequent and displays large interethnic variations, with an allelic frequency ranging from 14.6% in the French Caucasian population studied to less than 2% in Black African and Peruvian populations. This ethnic-related data might contribute to a better understanding of the variability in clinical outcome and/or dose adjustments of drugs that are IMPDH inhibitors such as mycophenolic acid.
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...
Linkage Disequilibrium Between IDUA kpnI -VNTR Haplotype in Mexican Patients with MPS-I
Background. The MPS-I is an autosomal recessive disorder caused by mutations in the IDUA gene that induce to a deficiency of glycosidase-L-iduronidase that is required for degradation of heparan and dermatan sulfate. This disorder expresses a wide range of clinical symptoms. Methods. KpnI (K) and VNTR (V) intragenic polymorphisms at the IDUA gene were studied in mestizo and Huichol Indian Mexican populations as well in 13 MPS-I patients. Data from Australian normal and MPS-I (2–4) individuals were also studied. Results. Genotypes for IDUA K and V sites in Mexicans were in agreement with Hardy-Weinberg expectations, except for site K in Huichols. Individually, allele frequency distributions were different (p 0.05) in the two normal groups for the V site. K-V haplotype frequency distributions (HFDs) in these two normal groups were also different as compared with normal Australians. In Mexican MPS-I patients, HFD was different (p 0.05) with respect to both Mexican normal groups, and non-different when compared with normal or MPS-I Australians. This can be taken as evidence of linkage disequilibrium between K-V polymorphism and MPS-I gene mutation(s) at the IDUA region. A similar finding was reported. However, disequilibrium in Mexicans was determined by haplo-types different from those in Australia. In Mexican MPS-I patients, haplotype K2-V1 is increased and K1-V3 decreased with respect to the Mexican mestizo (p 0.05), while in Australians, MPS-I patients had an increase of haplotypes K2-V2 and K1-V2 with respect to expected frequency. Conclusions. The similar HFD between Mexican and Australian MPS-I patients suggests a common genetic origin, that MPS-I mutations were introduced to Mexico by Spaniards, and that such mutations predate the dispersion between Mexican and Australian Caucasian ancestors. The differences in disequilibrium are explained rather by genetic drift.
Potential Genetic Causes of Heterogeneity of Treatment Effects
American Journal of Medicine, 2007
Nongenetic biologic and lifestyle-related factors, including age, sex, hepatic/renal function, diet/exercise practices, illness severity, smoking, and alcohol consumption habits can account for the heterogeneity of treatment effects (HTE). However, even when these factors are taken into account, considerable variation remains unexplained and could potentially be attributable to genetic differences between patients. Drug response may be dictated by variation in genes involved in both pharmacokinetic (PK) (absorption, distribution, metabolism, excretion [ADME]) and pharmacodynamic (PD) (receptors, ion channels, enzymes, immune system) pathways. Functional variants of the ADME genes can result in patients being poor, intermediate, efficient, or ultrarapid metabolizers of specific agents, thereby affecting efficacy and/or susceptibility to adverse drug reaction and necessitating individualized dosing. A well-documented example of ADME gene variation is the debrisoquine polymorphism, which is characterized by markedly different metabolism of numerous commonly prescribed drugs based on variants of the cytochrome P450 2D6 gene. Variants of genes regulating PD pathways cause altering of drug target pathways, which may affect efficacy in a more pronounced manner. Examples of gene variants affecting PD pathways include those coding for dopamine metabolism, synthesis, and transport. These gene variants may act independently, in combination with each other, and/or in combination with PK genes to affect drug response, for example to antipsychotic medications. Increased understanding of a patient's genotype and its corresponding effect on drug response would be useful to the practicing clinician in choosing an effective drug and in optimizing the dose in a timely manner.
Mycophenolic acid response biomarkers: A cell line model system-based genome-wide screen
International Immunopharmacology, 2011
Mycophenolic acid (MPA) is commonly used to treat patients with solid organ transplants during maintenance immunosuppressive therapy. Response to MPA varies widely, both for efficacy and drug-induced toxicity. A portion of this variation can be explained by pharmacokinetic and pharmacodynamic factors, including genetic variation in MPA-metabolizing UDPglucuronyltransferase isoforms and the MPA targets, inosine monophosphate dehydrogenase 1 and 2. However, much of the variation in MPA response presently remains unexplained. We set out to determine whether there might be additional genes that modify response to MPA by performing a genome-wide association study between basal gene mRNA expression profiles and an MPA cytotoxicity phenotype using a 271 human lymphoblastoid cell line model system to identify and functionally validate genes that might contribute to variation in MPA response. Our association study identified 41 gene expression probe sets, corresponding to 35 genes, that were associated with MPA cytotoxicity as a drug response phenotype (p < 1 × 10 −6). Follow-up siRNA-mediated knockdown-based functional validation identified four of these candidate genes, C17orf108, CYBRD1, NASP, and RRM2, whose knockdown shifted the MPA cytotoxicity curves in the direction predicted by the association analysis. These studies have identified novel candidate genes that may contribute to variation in response to MPA therapy and, as a result, may help make it possible to move toward more highly individualized MPA-based immunosuppressive therapy.
International Journal of Hematology and Therapy, 2015
Personalized medicine, one of special prevention and therapeutic strategies, is going to develop into clinical fields. Personalized medicine is directly tailored for physicians to prevent and care individual patient. It is often called as "the right treatment for the right person at the right time." Most successful examples of personalized prevention and treatments require a rational clinical genomic analysis. Following Research and Development (R&D) of clinical genomic techniques, here we introduce personalized targeted-therapy based on either detection of single nucleotide polymorphisms (SNP) or detection of universal single nucleotide variance (SNVs) at genomic level. According to clinical protocol of personalized targeted prevention and therapy, whole performance includes clinical sampling, SNP detection technology and diagnosis (universal and designed), SNP signature discovered by system modeling and sensitive targeted molecules/drugs uncovered by drug-banks with its confirmation. Now, after (A) simplified and designed SNP detection test is applied for clinical patients and (B) next generation sequencing for universal SNP detection is brought into the new field, both universal and designed SNP detection systems related with sensitive targeted molecules will make great contribution for further personalized prevention and treatment of tumor diseases, genetic diseases and uncured disease in nerve, endocrine and cardiovascular systems.
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.