PMID- 31636477 OWN - NLM STAT- MEDLINE DCOM- 20200226 LR - 20221207 IS - 2219-2840 (Electronic) IS - 1007-9327 (Print) IS - 1007-9327 (Linking) VI - 25 IP - 38 DP - 2019 Oct 14 TI - 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. PG - 5850-5861 LID - 10.3748/wjg.v25.i38.5850 [doi] AB - 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 x 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 x 10(8) RBC, P = 9.4 x 10(-5); 291.7 vs 217.6 pmol/8 x 10(8) RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 x 10(8) RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 x 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. CI - (c)The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved. FAU - Zhu, Xia AU - Zhu X AD - Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Chao, Kang AU - Chao K AD - Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Li, Miao AU - Li M AD - Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Xie, Wen AU - Xie W AD - Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, United States. FAU - Zheng, Hong AU - Zheng H AD - Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Zhang, Jin-Xin AU - Zhang JX AD - School of Public Health, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Hu, Pin-Jin AU - Hu PJ AD - Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Huang, Min AU - Huang M AD - Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Gao, Xiang AU - Gao X AD - Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. FAU - Wang, Xue-Ding AU - Wang XD AD - Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China. wangxd@mail.sysu.edu.cn. LA - eng PT - Journal Article PL - United States TA - World J Gastroenterol JT - World journal of gastroenterology JID - 100883448 RN - 0 (Biomarkers) RN - 0 (Guanine Nucleotides) RN - 0 (Immunosuppressive Agents) RN - 0 (Thionucleotides) RN - 15867-02-4 (6-thioguanylic acid) RN - E7WED276I5 (Mercaptopurine) RN - EC 2.6.1.- (NUDT15 protein, human) RN - EC 3.6.1.- (Pyrophosphatases) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Asian People/genetics MH - Biological Variation, Population/genetics MH - Biomarkers/blood MH - Child MH - Crohn Disease/blood/*drug therapy/immunology MH - Female MH - Guanine Nucleotides/*blood MH - Humans MH - Immunosuppressive Agents/*adverse effects MH - Leukopenia/chemically induced/*diagnosis MH - Male MH - Mercaptopurine/*adverse effects MH - Middle Aged MH - Polymorphism, Single Nucleotide MH - Predictive Value of Tests MH - Prognosis MH - Pyrophosphatases/*genetics MH - Reference Values MH - Retrospective Studies MH - Thionucleotides/*blood MH - Young Adult PMC - PMC6801191 OTO - NOTNLM OT - Crohn's disease OT - Nucleoside diphosphate-linked moiety X-type motif 15 OT - Thioguanine nucleotide levels OT - Thiopurine-induced leukopenia COIS- Conflict-of-interest statement: The authors declare no competing financial interests related to this study. EDAT- 2019/10/23 06:00 MHDA- 2020/02/27 06:00 PMCR- 2019/10/14 CRDT- 2019/10/23 06:00 PHST- 2019/07/24 00:00 [received] PHST- 2019/09/05 00:00 [revised] PHST- 2019/09/11 00:00 [accepted] PHST- 2019/10/23 06:00 [entrez] PHST- 2019/10/23 06:00 [pubmed] PHST- 2020/02/27 06:00 [medline] PHST- 2019/10/14 00:00 [pmc-release] AID - 10.3748/wjg.v25.i38.5850 [doi] PST - ppublish SO - World J Gastroenterol. 2019 Oct 14;25(38):5850-5861. doi: 10.3748/wjg.v25.i38.5850.