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4CPS-147 Determination of tpmt and nudt15 polymorphisms in a patient with common variable immunodeficiency

ABSTRACT: Background The lack of activity in thiopurine-methyltrasnferase (TPMT) is related to severe toxicity in the use of thiopurines (azathioprine, 6-mercaptopurine and thioguanine). This lack of activity is often due to genetic polymorphisms located at TPMT, and recently demonstrated in NUDT15 genes. Purpose To describe the case of a patient with inflammatory elbow disease (IBD) and a congenital immunodeficiency who is being prescribed azathioprine and who has been tested for TPMT and NUDT15 genetic polymorphisms determination. Material and methods Male, 21-years-old patient who was diagnosed at the age of eight years with common variable immunodeficiency (CVI) with gastrointestinal manifestations. In 2002 the patient was diagnosed with ulcerative jejunitis and after receiving different first-line treatments (mesalazine and corticosteroid) was not able to obtain a good control of the disease. Thus, his doctor decided to start treatment with azathioprine. Given the risk of severe immunosuppression derived from the CVI and the use of azathioprine the decision was taken to make a genetic polymorphism analysis of TPMT (rs2842934, rs2842934, rs1800460, rs1800584 and rs1142345) and NUDT15 (rs116855232, rs147390019, rs554405994 and rs186364861). DNAg was carried out using the Ramos et al. (2015) method and the characterisation was implemented using PCR and DNA sequencing. Results The patient showed a wild-type genetic profile for the polymorphism analysed. Consequently, he was prescribed with azathioprine with a complete dosage of 100?mg per day (2?mg/kg/d). After 3 months of treatment the patient had maintained a neutrophil normal range (higher than 2000 neutrophils per mm3) and, in addition, achieved a good control of the illness. Therefore the patient continued with the azathioprine at the usual dosage. Conclusion The integration of pharmacy services in the multidisciplinary teams is facilitating the implementation of pharmacogenetics in daily clinical practice in our hospitals. This kind of determinations provides the prescription clinicians with tools to improve the effectiveness and safety of treatments. In this case we have given an example in which the determination of a genetic WT profile for TPMT and NUDT15 has allowed for the full use of azathioprine dosage from the beginning of the treatment, which therefore resulted in an adequate control of the disease. No conflict of interest

SUBMITTER: Gil S

PROVIDER: S-EPMC7535486 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Project description:To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.There were 219 patients with IBD (160 men and 59 women), including 39 who were confirmed with ulcerative colitis (UC), 176 with Crohn's disease (CD) and 4 with undetermined IBD (UIBD). There were 44 patients (20.1%) with mutant genotype of NUDT15 (C/T); among them, 16 received AZA, and 8 (50%) developed leukopenia. There were 175 patients (79.7%) with wild genotype of NUDT15 (C/C); among them, 64 received AZA, and 11 (17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C (P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G (1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 patients received AZA, and 18 (22.8%) developed leukopenia, and there was no significant difference from those with A/G (P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1% (P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.

Project description:Background: Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. Methods: The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: ITPA 94C > A (rs1127354) and IVS2+21A > C (rs7270101), TPMT*2 238G > C (rs1800462), TPMT*3B 460G > A (rs1800460) and *3C 719A > G (rs1142345), and NUDT15 415C > T (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. Results: As expected, TPMT and NUDT15 variants were uncommon. As for ITPA, both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for 94C > A and 0.14 for IVS2+21A > C in the Lebanese only (N = 121), and of 0.01 for either ITPA polymorphism in Kurds. The most significant toxic effects were depicted with the NUDT15 polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for TPMT*3A polymorphism, followed by 65.33% for two ITPA risk allele carriers and 74% for one ITPA risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. Conclusions: These data confirm the predictive role of TPMT, NUDT15, and ITPA in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of ITPA variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for ITPA variants in conjunction with TPMT and NUDT15 prior to 6-MP therapy in these children.

Project description:Background Genetic-polymorphisms in thiopurine-methyltransferase (TPMT) and Nudix-hydrolase15 (NUDT15) have been related to higher risk of toxicity associated with administration of 6-mercaptopurine(6-MP). Purpose To describe the implementation of polymorphisms determination in TPMT and NUDT15 in paediatric patients by a simple and economic method. Material and methods A multi-centre, prospective, observational study with a expected duration of 32 months was carried out. Participants were patients younger than 18 years who received treatment with 6-MP. Single nucleotide polymorphisms (SNPs) analysed were: TPMT (rs1800462;rs1800462; rs1800460;rs1142345 and rs1800584) and NUDT15 (rs116855232;rs147390019;rs554405994 and rs186364861). DNAg extraction was carried out using the Ramos et al. method and genotyping was done using PCR and subsequent DNA sequencing. The study was approved by the hospital’s Ethical Committee (CEIC). Legal guardians were requested to sign an informed consent form prior to inclusion. Results During the first 8 months, nine patients were included, with an average age of 3.5 (1–18)and 62.5% of them were females. Six of the included patients (66.6%) were diagnosed with acute lymphoblastic leukaemia, two with non-Hodgkin’s lymphoma (22.2%) and one with acute myeloid leukaemia. Eighty-one genetic-determinations were carried out. None of the patients presented a high-risk genotype for the TPMT gene. One of the children showed a medium-risk genotype *1/*3B,*1/*3C, but after 3 months of treatment with 6-MP he has not shown toxicity. This patient also showed a wild-type genotype for the NUDT15 gene which could explain the absence of toxicity during the treatment. Another patient has shown a heterozygous genotype for the rs116855232 and rs554405994 (NUDT15 gene). This patient has not already received treatment with 6-MP so we cannot evaluate the mutation influence yet. Conclusion Althought we have not found patients with high-risk polymorphisms in TPMT yet, we support the implementation of this screening because the presence of this genotypes is related to severe toxicity and even death-risk in these patients. We also have completed the procedure with the determination of mutations in the NUDT15 gene, increasing the probability of identifying patients with low tolerance to 6-MP. To our knowledge, the present study is the first to evaluate the effect of polymorphisms in both TPMT and NUDT15 in the treatment with 6-MP, so definitive results could cidentify how those polymorphisms affect the toxicity related to 6-MP. References and/or Acknowledgements 1. Ramos-Díaz. 2015May;75(5):1095–8. 2. Kotur, et al. 2015;16(15):1701–12. No conflict of interest

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4CPS-147 Determination of tpmt and nudt15 polymorphisms in a patient with common variable immunodeficiency

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