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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
- Source :
- World Journal of Gastroenterology
- Publication Year :
- 2019
- Publisher :
- Baishideng Publishing Group Inc., 2019.
-
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.
- 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
Subjects
Details
- ISSN :
- 10079327
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- World Journal of Gastroenterology
- Accession number :
- edsair.doi.dedup.....646389bc2d8a54238b7056dbdfea1da2