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IMPDH1 Gene Polymorphisms and AssociationWith Acute Rejection in Renal TransplantPatients J Wang1, JW Yang2, A Zeevi3, SA Webber4, DM Girnita3, R Selby5, J Fu1, T Shah2, V Pravica1,2,IV Hutchinson1,2,5 and GJ Burckart1 Inosine 50-monophosphate dehydrogenase 1 (IMPDH1) catalyzes the rate-limiting step of the de novo pathway forpurine synthesis and is a major target of the immunosuppressive drug mycophenolic acid (MPA). Few variants of theIMPDH1 gene have been reported. The objective of this study was to identify and characterize IMPDH1 variants todetermine whether genetic variation contributes to differences in MPA response and toxicity in transplant patients.
Seventeen genetic variants were identified in the IMPDH1 gene with allele frequencies ranging from 0.2 to 42.7%.
In this study, 191 kidney transplant patients who received mycophenolate mofetil were genotyped for IMPDH1. Twosingle-nucleotide polymorphisms, rs2278293 and rs2278294, were significantly associated with the incidence of biopsy-proven acute rejection in the first year post-transplantation. Future studies of the multifactorial nature of acute rejectionmust consider IMPDH1 polymorphisms in MPA-treated patients.
Inosine 50-monophosphate dehydrogenase (IMPDH) (EC is the rate-limiting enzyme in the pathway of IMPDH210,11 and has substrate affinities and Ki values that de novo biosynthesis of guanine by driving inosine monopho- are virtually indistinguishable.12 In an IMPDH1-knockout sphate (IMP) to xanthosine monophosphate with the mouse model, IMPDH1 deletion inhibited T-cell activation reduction of nicotinamide adenine dinucleotide (NAD). This in response to anti-CD3 and anti-CD28 antibodies.13 enzyme is the target of mycophenolic acid (MPA), the active Although MPA has been shown to inhibit the activities of constituent of the prodrug mycophenolate mofetil (MMF), both IMPDH1 and IMPDH2 isoforms in vitro, IMPDH2 is which is widely used clinically to prevent allograft rejection 4.8 times more sensitive to MPA inhibition than IMPDH1.14 following solid organ transplantation.1 MPA is also used as Several mutations in the IMPDH-binding site confer an immunomodulator in immune-related diseases such as variable degrees of resistance to MPA in the parasite AIDS, lupus nephritis, myasthenia gravis, and immune Tritrichomonas foetus, and varying drug-sensitive forms of thrombocytopenic purpura.2–6 Unlike other cell types, which this enzyme have been detected in Saccharomyces cerevisiae.
can use the salvage pathway for purine synthesis, lympho- However, few studies have been reported on IMPDH gene cytes are exclusively dependent upon the de novo pathway variants in humans.15–17 Recent findings have shown that catalyzed by IMPDH for the generation of guanosine mutations in IMPDH1 cause autosomal-dominant retinitis nucleotide.7,8 MPA uncompetitively, selectively, and reversi- pigmentosa.18,19 No other changes in IMPDH1 that result in bly inhibits this pathway and therefore inhibits cell a change in the genotype–phenotype relationship have been IMPDH has two isoforms named IMPDH1 and IMPDH2, As maintenance of the balance between rejection and over- and the genes that encode these proteins are located on two immunosuppression is difficult, pharmacokinetic and pharmaco- different chromosomes.9 IMPDH1 is located on chromosome dynamic monitoring of MMF have been proposed to 7 region q32.1 and is constitutively expressed in all tissues.
optimize drug dosage and the administration schedule.20 1Department of Pharmacy, University of Southern California, Los Angeles, California, USA; 2The National Institute of Transplantation, Los Angeles, California, USA;3Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 4Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania,USA; 5Department of Surgery, University of Southern California, Los Angeles, Califo rnia, USA. Correspondence: GJ Burckar t Received 29 April 2007; accepte d 4 July 2007; advance online publication 12 Septe mber 2007. CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 5 | MAY 2008 711 Hale et al.21 previously reported that the area under curve (AUC) of MPA is inversely associated with the likelihood of To examine IMPDH1 genetic variation, 17 exons and the allograft rejection after renal transplantation in patients intron–exon boundary regions were initially sequenced from receiving MMF. The relationship between MMF pharmaco- 30 genomic DNA samples from liver transplant patients.
kinetic parameters and the risk of adverse effects is not as well Seventeen genetic variants were identified in the IMPDH1 defined. Considering the significant variability in the effects gene. Eleven single-nucleotide polymorphisms (SNPs), in- of a given concentration of MPA, the therapeutic range for cluding four exonic variants and seven intronic SNPs with the desired pharmacologic effect without adverse effects in relatively high allele frequencies, were subjected to TaqMan most patients is difficult to discern.22 Interindividual SNP assay using an ABI 7900 Real-Time PCR System. The variability in IMPDH activity has been observed in healthy identified polymorphisms and their frequencies are listed in volunteers as well as transplant patients.23,24 Pharmaco- lists the demographic data for the 191 renal dynamic monitoring of IMPDH activity has been proposed, transplant patients who were divided into patients with and and a significant relationship has been reported between without an episode of biopsy-proven acute rejection in the pretransplant IMPDH activity and clinical outcome after first postoperative year. No significant demographic diffe- renal transplantation.24 However, MPA is most frequently rence was found between the group with rejection and administered to transplant patients without monitoring MPA without rejection with respect to age at transplantation, plasma concentrations, IMPDH concentrations, or other weight, height, gender, and race/ethnicity (P40.05). All of the SNPs genotyped were in the Hardy–Weinberg equilibrium The considerable variability in baseline IMPDH activity and MPA response may logically be under the control of Two novel non-synonymous variants, Asp301Asn and genetic variation within the IMPDH genes or in gene Gly519Arg, were identified in exons 10 and 15 of IMPDH1.
expression. Analysis of genetic variants could provide the The effects of these polymorphisms were determined on explanation for the variability of IMPDH activity and MMF IMPDH production (see Supplementary Material, Table S4 response in transplant patients. Therefore, the objective of and Figures S3 and S4), and neither was found to change this study was to identify IMPDH1 genetic variants in renal transplant patients and to retrospectively look for the Biopsy-proven acute rejection occurred in 15% of patients association of these polymorphisms with leukopenia or in the first postoperative year, which approximates the rate of biopsy-proven acute rejection in renal transplant patients rejection observed currently in transplant centers in the United States with a high percentage of high-risk patients.25 Table 1 Genetic variants of IMPDH1 in transplant patients detected by bidirectional DNA sequencing IMPDH, inosine 50-monophosphate dehydrogenase; SNP, single-nucleotide polymorphism. aThe position is relative to ATG start site with the A as nucleotide +1 and based onmRNA sequence from GenBank accession number NM_000883. bThe frequencies were reported by GenBank. cAmino-acid (AA) change with its position shown in middle(NP_000874). Non-synonymous change is shown in bold. dTagging SNPs. eFrequencies based on sequencing in transplant patients.
VOLUME 83 NUMBER 5 | MAY 2008 | Table 2 Demographic characteristics of the kidney transplant patients MPA, mycophenolic acid. aData were represented as mean+SD.
Two SNPs, rs2278293 and rs2278294, were significantly associated with the incidence of biopsy-proven acute Numerous SNPs have now been associated with acute rejection in the first year post-transplantation rejection after renal transplantation. Most of these SNPs Po0.05, w2). The prognostic value of each of these SNPs in have been part of the transplant immune response and predicting biopsy-proven rejection exceeded 50% for both include cytokines, chemokines, adhesion molecules, and the positive predictive value and the negative predictive value growth factors. The pharmacogenetic factors affecting drug . Both of these SNPs are intronic, and one is a bioavailability, direct action, and disposition in organ component of a haplotype block. The odds ratio by logistic transplant patients have not been associated with acute regression analysis was 0.34 for SNP rs2278293 (95% rejection previously, with the exception of an ABCB1 confidence interval: 0.15–0.76; P ¼ 0.008) and 0.40 for rs2278294 (95% confidence interval: 0.18–0.89; P ¼ 0.02).
Plasma concentrations of MPA are affected by a number of Leukopenia occurred in approximately 32% of the gene polymorphisms. Both the glucuronidating uridine 50- patients receiving MPA in the first postoperative year diphospho-glucuronosyltransferase (UGT) enzymes29–31 and . In previous reports of leukopenia in MPA-treated the drug transporter multidrug resistance-associated protein-2 transplant patients, leukopenia occurs in 25.9–39.3% of (MRP2)32 polymorphisms may affect MPA plasma concen- patients, depending on the criteria for classifying leuko- trations. P-glycoprotein, MRP2, and the organic anion- penia.26 Leukopenia was not associated with any of the transporting polypeptide (OATP) transporters may play IMPDH1 SNPs. We observed leukopenia in the one variant a potential role in MPA disposition, so it is not surprising IMPDH2 L263F patient in accordance with our previous that considerable variability in MPA pharmacokinetics has been observed in transplant patients.33shows that Six tagging SNPs were selected to present the two the critical step in exerting the effect of MPA is at IMPDH, which is controlled by IMPDH1 and IMPDH2.
haplotypes, rs11770116–rs2288548 and rs2278294–rs2228075, Our previous explorative study showed that IMPDH2 is were also examined for their influence on leukopenia or acute more conserved than its isoform IMPDH1. Although we rejection within 1-year post-transplantation . No identified a novel variant L263F that affects enzyme activity haplotype association was found for leukopenia or acute in IMPDH2,27 its rare frequency precludes it from having a large effect in a small patient population. Another SNP, The genotype distribution for all of the SNPs, with one rs11706052, was not associated with the incidence of biopsy- exception, was not statistically different between the Hispanic proven rejection in this study. Owing to the low frequency of and non-Hispanic patients (Table S2). The distribution was the L263F variant, further studies in larger populations significantly different for rs2288553, but this SNP was not would be needed to define its impact on clinical outcome.
significantly associated with either acute rejection or The IMPDH monomer contains eight-stranded a/b barrels, which are the core domain of the IMPDH1 protein.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 5 | MAY 2008 Table 3 The association of IMPDH1 and IMPDH2 SNPs with biopsy-proven rejection and leukopenia in kidney transplant patients IMPDH, inosine 50-monophosphate dehydrogenase; SNP, single-nucleotide polymorphism. *Po0.05 for rejection by w2.
Table 4 Prognostic valuea of the IMPDH1 polymorphism for determining biopsy-proven rejection in kidney transplant patientstreated with MPA CI, confidence interval; IMPDH, inosine 50-monophosphate dehydrogenase; MPA, mycophenolic acid. aMean value and 95% CI.
This area contains the entire machinery for enzyme catalytic non-synonymous SNPs encode for G519R and D301N, which activity, flanked by a subdomain composed of two regions are both located at the flanking subdomain, and the in vitro similar to the cystathionine b-synthase gene (CBS domain) enzyme kinetic assay and filter-binding assay indicated that (Figure S2). The subdomain of IMPDH can bind with the functional consequences of these variants are minor.
nucleic acid with nanomolar affinity, but the function of this A novel IMPDH1 gene mutation (Arg231Pro) is reported DNA-binding property is yet to be determined. Our novel to be associated with a severe form of autosomal-dominant VOLUME 83 NUMBER 5 | MAY 2008 | for approximately 2% of families with autosomal-dominantretinitis pigmentosa, and de novo IMPDH1 mutations are alsorare causes of isolated Leber congenital amaurosis.35 TwoIMPDH1 variants, Arg105Trp and Asn198Lys, were reportedin two patients with isolated Leber congenital amaurosis. TheAsp226Asn mutation is associated with a severe early-onsetform of retinal degeneration. Retinitis pigmentosa is a rare disease, and we did not observe these variations in our transplant patients. The only previous report relating to transplant patients was that a 9-bp insertion within theIMPDH1 promoter region was found in a patient exhibiting severe azathioprine resistance, possibly by reducing the Hispanic renal transplant patients are considered to be high-risk patients and have a higher rate of graft failure based on United Network for Organ Sharing (UNOS) data than dothe Caucasian renal transplant patients.37 The rates of biopsy- proven acute rejection have varied in high-risk renal transplant populations given antibody-induction therapyfrom 15.6%38 to 26.4%39 but are as low as 5% at individualcenters.40 No evidence could be found in this study that the Figure 1 LD patterns and haplotype blocks in kidney transplant patientswere defined according to the ‘‘solid spine of LD’’ setting in Haploview 3.2 inclusion of a significant number of Hispanic patients software, which is under the analysis criteria solid spine of LD40.8. A influenced our analysis of IMPDH1 polymorphisms and standard color scheme is used to display LD pattern, with dark gray for very biopsy-proven acute renal transplant rejection.
strong LD (log of likelihood odds ratio, logarithm of odds (LOD)X2, D0 ¼ 1), The accurate assessment of those transplant patients who white for no LD (LODo2, D0o1), and bright gray and shades of gray for are at risk for the development of acute rejection will require intermediate LD (LODX2, D0o1); increasing intensity of gray indicatesincreasing degrees of LD.
looking at a multiplicity of immune and pharmacologicfactors. In this population of renal transplant patients,IMPDH1 SNPs were prognostic of the development of biopsy-proven acute rejection in the first postoperative year.
The mechanism of association between IMPDH1 polymorph- isms and acute rejection is still to be determined. One possible explanation is their linkage to other SNPs that may control IMPDH1 mRNA expression, enzyme activity, and ultimately lymphocyte proliferation. Future prospective studies should examine the mechanism by which IMPDH1 polymorphisms might affect the immunologic response in transplant patients receiving MPA. Both pharmacogenomicand immunogenetic factors will have to be considered in developing treatment algorithms for transplant patients.41 This study supports the inclusion of IMPDH1 polymorph- isms as one factor that must be tested in developing a panel of gene polymorphisms used to assess the risk of acute Figure 2 A graphic presentation of the involvement of multiple enzymes rejection for transplant patients being treated with MPA.
and transporters affecting the action of MPA on lymphocyte proliferation.
Each of the polymorphisms designated by an asterisk may affect the plasma concentrations of MPA either directly or through the enterohepatic In the IMPDH-sequencing initial study, 30 recycling of mycophenolic acid glucuronide (MPAG), with the exception of DNA samples of liver transplant patients at the University of IMPDH. IMPDH is the target of MPA in de novo purine synthesis in Southern California were screened to identify SNP candidates in IMPDH1. In the following study, we genotyped 191 kidneytransplant patients from the National Institute of Transplantation(St Vincent’s Medical Center) in Los Angeles. All kidney transplant retinitis pigmentosa. Five different IMPDH1 variants, patients had been treated from the time of transplantation with Thr116Met, Asp226Asn, Val268Ile, Gly324Asp, and His372- tacrolimus, MMF, and prednisone-based immunosuppression, withthe exception of five patients who received cyclosporine in place of Pro, have been identified in eight autosomal-dominant tacrolimus. The therapeutic serum target level was 5–15 mg/ml for retinitis pigmentosa families, but their functional significance tacrolimus and 100–200 mg/ml for cyclosporine. MMF doses were remains to be defined.18,19,34 Mutations in IMPDH1 account adjusted based upon patient’s tolerance of the adverse effects of the CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 5 | MAY 2008 drug with respect to gastrointestinal side effects and development of Allele and genotype frequencies were calculated leukopenia. The following inclusion and exclusion criteria were used for each locus and tested for Hardy–Weinberg equilibrium using for the renal transplant study: (1) patients who underwent renal (
transplantation from 2000 to 2005, with available DNA, and had Determination of linkage disequilibrium (LD), tagging SNPs, post-transplant survival more than 1 year with follow-up informa- haplotype blocks, and frequencies were performed by using tion available; (2) patients must have been on MMF for at least 1 Haploview version 3.2. Haplotype blocks were defined according year; and (3) patients must not have been receiving antiviral to the ‘‘solid spine of LD’’ setting in Haploview 3.2 software, which is (valganciclovir, ganciclovir), anticancer, or other leukopenia-causing under the analysis criteria solid spine of LD40.8.
medications at the time when leukopenia was recorded.
Each variant in IMPDH1 underwent univariate analysis for the The protocols were approved by the institutional review boards difference of allele distribution between patients with or without of the University of Southern California and St Vincent’s Medical leukopenia and between patients with or without rejection within Center in Los Angeles. All patients or guardians provided informed 1-year post-transplantation by w2 test. Considering the low written consent to undergo genotyping. Anticoagulated venous frequency of the minor alleles, we combined the homozygous blood was obtained from each patient, and DNA was extracted from variant with the heterozygous patients. Therefore, the presence or whole blood using a commercially available DNA extraction absence of the variant alleles, instead of genotype, was compared in procedure (Qiagen, Valencia, CA). Sequencing and genotyping were this population. Multiple logistic regression analysis was performed performed in patients who had been previously transplanted, and all to examine the association between IMPDH1 variants and acute patient information was collected retrospectively. Patients were rejection in patients. For SNPs with P-value o0.05, clinical managed according to the standard transplant center protocol, prognostic values (sensitivities, specificities, negative and positive which did not include monitoring of MPA plasma concentrations.
predictive values) were assessed for their association with acute At most transplant centers, MPA doses are adjusted based upon rejections occurring in the first postoperative year. All P-values patient’s tolerance of the adverse effects of the drug with respect to o0.05 were considered as significant. Statistical analysis was gastrointestinal side effects and the development of leukopenia.
performed using the SPSS software program version 14.0 forWindows (SPSS, Chicago, IL).
SNP identification in the IMPDH1 gene was The incidence of both leukopenia and rejection was treated as a performed by PCR amplification followed by bidirectional direct dichotomous trait. Patients with a white blood cell count 43,000/ml DNA sequencing, as described previously.27 PCR was carried out in were considered as not having leukopenia, and patients with a white a total volume of 50 ml using 50 ng of genomic DNA, 5 pmol of each blood cell p3,000/ml during MPA treatment were considered as forward and reverse primer (Sigma, St Louis, MO), 0.2 mM dNTP having leukopenia. Further subgroup analysis was carried out using (Promega, Madison, WI), 1 Â PCR buffer, and 1.5 U of thermo- the grades of leukopenia described by the Southwest Oncology stable Taq DNA polymerase and Tgo DNA polymerase with proofreading activity and high fidelity (Expand 20 kbPLUS PCRSystem; Roche Applied Science, Penzberg, Germany). The primers SUPPLEMENTARY INFORMATION is linked to the online version of the used are described in Table S1. The PCR process included initial denaturation at 921C for 2 min and 10 cycles of denaturation at921C for 10 s, annealing at 571C for 30 s, and synthesis at 681C for 7 min followed by additional 25 cycles of denaturation at 921C for This work was supported by 5P50 HL074732 from the National Heart Lung 10 s, annealing at 571C for 30 s, and synthesis at 681C for 7 min, with and Blood Institute, National Institutes of Health.
the time extended by 10 s for each successive cycle. The finalelongation was carried out for 5 min at 721C. Amplified PCR products were purified by using the Qiagen PCR purification kit The authors declared no conflict of interest.
(Qiagen) and sequenced by conventional means using the BigDyeTerminator Cycle Sequencing Ready Reaction Kit on ABI 377 XL ª 2007 American Society for Clinical Pharmacology and Therapeutics Sequencer (Applied Biosystems, Foster City, CA). SNPs were Allison, A.C. & Eugui, E.M. Mycophenolate mofetil and its mechanisms identified by transferring the chromatograms to sequence assembly of action. Immunopharmacology 47, 85–118 (2000).
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