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3 results on '"Thiopurine-induced leukopenia"'

2. Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Author

Xiang Gao, Kang Chao, Wen Xie, Jin-Xin Zhang, Min Huang, Pinjin Hu, Miao Li, Xia Zhu, Zheng Hong, and Xueding Wang

Subjects
Crohn’s disease, Male, Thiopurine-induced leukopenia, Gastroenterology, 0302 clinical medicine, Crohn Disease, Reference Values, Genotype, Pyrophosphatases, Child, Crohn's disease, Leukopenia, Thiopurine methyltransferase, biology, Mercaptopurine, 6-thioguanine nucleotide, hemic and immune systems, General Medicine, Middle Aged, Prognosis, Guanine Nucleotides, 030220 oncology & carcinogenesis, Toxicity, Female, 030211 gastroenterology & hepatology, medicine.symptom, Immunosuppressive Agents, Adult, medicine.medical_specialty, Adolescent, Polymorphism, Single Nucleotide, Young Adult, 03 medical and health sciences, Asian People, Retrospective Study, Predictive Value of Tests, Nucleoside diphosphate-linked moiety X-type motif 15, Internal medicine, medicine, Humans, Aged, Retrospective Studies, business.industry, Nucleoside diphosphate, Thionucleotides, medicine.disease, Biological Variation, Population, biology.protein, Thioguanine nucleotide levels, business, Nucleoside, Biomarkers
Abstract

Background Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes? Aim To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes. Methods Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured. Results A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. Conclusion The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

Published
2019

3. Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn's disease patients.

Author

Zhu X, Chao K, Li M, Xie W, Zheng H, Zhang JX, Hu PJ, Huang M, Gao X, and Wang XD

Subjects
Adolescent, Adult, Aged, Asian People genetics, Biological Variation, Population genetics, Biomarkers blood, Child, Crohn Disease blood, Crohn Disease immunology, Female, Humans, Leukopenia chemically induced, Male, Middle Aged, Polymorphism, Single Nucleotide, Predictive Value of Tests, Prognosis, Reference Values, Retrospective Studies, Young Adult, Crohn Disease drug therapy, Guanine Nucleotides blood, Immunosuppressive Agents adverse effects, Leukopenia diagnosis, Mercaptopurine adverse effects, Pyrophosphatases genetics, Thionucleotides blood
Abstract

Background: Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 ( NUDT15 ) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?, Aim: To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes., Methods: Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured., Results: A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 10 8 red blood cells (RBC), which was not different from that of patients without TIL ( P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC ( n = 342) and CT ( n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 10 8 RBC, P = 9.4 × 10 -5 ; 291.7 vs 217.6 pmol/8 × 10 8 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 10 8 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 10 8 RBC for the CC and CT groups, respectively., Conclusion: The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended., Competing Interests: Conflict-of-interest statement: The authors declare no competing financial interests related to this study., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Published
2019
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