Dataset Information

Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease.

ABSTRACT: The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn's disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD. We enrolled 165 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were carried out every 2-3 months. We measured thiopurine metabolites levels and genotyped NUDT15 and TPMT. During the median 12-month observational period, 95 (67.9%) patients exhibited clinical response and 45 (32.1%) did not respond to the treatment. The median 6-TGN level was significantly higher in responders than in non-responders (P < 0.001). The odds ratio of patients with a 6-TGN level ?230 pmol/8 × 108 red blood cells for showing a clinical response was 4.63 (95% CI 1.62-11.9). NUDT15 variant types were strongly associated with developing leukopenia. Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with an average reduction of 88.2% (range, 84-94%) from the baseline white blood cell count at 4 weeks. Our findings support the role of therapeutic drug monitoring in thiopurine maintenance treatment to optimize thiopurine therapy, especially, for non-responding CD patients. Thiopurine treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia.

SUBMITTER: Lee JH

PROVIDER: S-EPMC5716599 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease.

Lee Ji Hyeon JH Kim Tae Jun TJ Kim Eun Ran ER Hong Sung Noh SN Chang Dong Kyung DK Choi Li-Hwa LH Woo Hye In HI Lee Soo-Youn SY Kim Young-Ho YH

PloS one 20171205 12

The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn's disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia i ...[more]

PMID: 29206869

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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:BackgroundNUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity that results in therapeutic failure in pediatric acute lymphoblastic leukemia (ALL). However, many patients with both wild-type (WT) NUDT15 and TPMT still suffer from thiopurine toxicity and therapeutic failure.MethodsWhole-exome sequencing was done for discovery (N = 244) and replication (N = 76) cohorts. Age- and sex-adjusted multiple regression analyses of both WT patients were performed to identify (p < 0.01, N = 188 for discovery) and validate (p < 0.05, N = 52 for replication) candidate variants for the tolerated last-cycle 6-mercaptopurine (6-MP) dose intensity percentage (DIP). Both independent and additive effects of the candidate variants on well-known NUDT15 and TPMT were evaluated by multigene prediction models.ResultsAmong the 12 candidate variants from the discovery phase, the rs3821169 variant of the gene encoding Cysteine-Rich Transmembrane BMP Regulator 1 (CRIM1) was successfully replicated (p < 0.05). It showed high interethnic variability with an impressively high allele frequency in East Asians (T = 0.255) compared to Africans (0.001), Americans (0.02), Europeans (0.009), and South Asians (0.05). Homozygote carriers of the CRIM1 rs3821169 variant (N = 12, 5%) showed significantly lower last-cycle 6-MP DIPs in the discovery, replication, and combined cohorts (p = 0.025, 0.013, and 0.001, respectively). The traditional two-gene model (NUDT15 and TPMT) for predicting 6-MP DIP < 25% was outperformed by the three-gene model that included CRIM1, in terms of the area under the receiver operating characteristic curve (0.734 vs. 0.665), prediction accuracy (0.759 vs. 0.756), sensitivity (0.636 vs. 0.523), positive predictive value (0.315 vs. 0.288), and negative predictive value (0.931 vs. 0.913).ConclusionsThe CRIM1 rs3821169 variant is suggested to be an independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.

Project description: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

Dataset Information

Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease.

Publications

Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's disease.

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