Dataset Information

Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease.

ABSTRACT: 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.

SUBMITTER: Wang HH

PROVIDER: S-EPMC5829157 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Comparison of <i>TPMT</i> and <i>NUDT15</i> polymorphisms in Chinese patients with inflammatory bowel disease.

Wang Hong-Hui HH He Ying Y Wang Hong-Xian HX Liao Cheng-Ling CL Peng Yu Y Tao Li-Jian LJ Zhang Wei W Yang Hui-Xiang HX

World journal of gastroenterology 20180201 8

<h4>Aim</h4>To observe gene polymorphisms of <i>TPMT</i> and <i>NUDT15</i>, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).<h4>Methods</h4>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 <i>TPMT</i> and <i>NUDT15</i> by pyrosequencing at the Department o ...[more]

PMID: 29491687

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Project description:The single nucleotide polymorphism (SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease (IBD) treated with thiopurines.Ninety-six Japanese patients with IBD were enrolled. Genotyping for the NUDT15 and TPMT genes was performed using Custom TaqMan SNP genotyping assays or Sanger sequencing. The changes in white blood cell (WBC) count, mean corpuscular volume (MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were evaluated.Genetic variants of exon 1 and exon 3 of NUDT15 were identified in 24 of 96 patients (25.0%). C.52G > A and c.36_37insGGAGTC in exon 1 were found in three patients each. All three patients with c.36_37insGGAGTC in exon 1 were heterozygotes of p.Arg139Cys in exon 3. Eighteen patients had p.Arg139Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases (n = 24), and was significantly lower at 6, 8, 10, and 16 wk (P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk (P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases (P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk (P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wild-type and mutated cases. TPMT mutations were not found in any of the patients.Mutations in exon 1 of NUDT15 also affect thiopurine-induced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia in more detail, investigation of SNPs in both exon 1 and exon 3 of NUDT15 is needed.

Project description:ImportanceUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).ObjectiveTo identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).Design, setting, and participantsCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.ExposuresGenetic variants associated with TIM.Main outcomes and measuresThiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.ResultsAmong 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.Conclusions and relevanceAmong patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

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

Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease.

Publications

Comparison of <i>TPMT</i> and <i>NUDT15</i> polymorphisms in Chinese patients with inflammatory bowel disease.

Similar Datasets

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