- •Genetic variance of TPMT is not a determinant for AZA-induced leukopenia in Korea
- •In Korea, the NUDT15 p.R139C variant is common and may predict AZA-induced leukopenia
- •Also, this variant of homozygote primarily serves as a risk factor for early rather than late-developing leukopenia of severe grade, along with the associated alopecia.
Azathioprine (AZA)-induced leukopenia is a relatively common complication in Korean patients. In addition to variation in TPMT (thiopurine S-methyltransferase), the NUDT15 p.R139C variant was recently identified to have a strong association with AZA-induced leukopenia. We investigated these associations in Korean patients undergoing AZA treatment with various neurological diseases. Among 84 enrolled patients, 20 (23.8%; 7 early, 13 late) exhibited leukopenia. The NUDT15 p.R139C variant was associated with leukopenia (OR: 11.844, 95% CI 3.984–36.024, p = 1.327 × 10−5). The allelic frequency of NUDT15 p.R139C was as high as 10.7% and the frequency of the C/C, C/T, and T/T genotypes was 84.5, 10.7, and 5.9%, respectively. All T/T homozygous patients (5/5) developed early severe-grade leukopenia (white blood cells <1000 mm−3) and severe alopecia. NUDT15 p.R139C was strongly associated with early leukopenia and severe alopecia (OR for early leukopenia: 107.624, 95% CI 18.857–614.250, p = 1.403 × 10−7, OR for severe alopecia: 77.152, 95% CI 17.378–342.526, p = 1.101 × 10−8). The sensitivity and specificity for predicting AZA-induced early leukopenia were 85.7% and 92.2%, respectively. Therefore, the NUDT15 p.R139C variant is common and strongly associated with AZA-induced early leukopenia and severe alopecia in Korean patients with various neurological diseases.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of the Neurological Sciences
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Azathioprine: clinical pharmacology and current indications in autoimmune disorders.BioDrugs. 1998; 9: 33-47
- Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine.Ann. Intern Med. 1998; 129: 716-718
- The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.Pharmacogenetics. 1999; 9: 37-42
- Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy.Gastroenterology. 2000; 118: 1025-1030
- Monitoring and safety of azathioprine therapy in inflammatory bowel disease.Pediatr. Gastroenterol. Hepatol. Nutr. 2013; 16: 65-70
- Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study.J. Clin. Gastroenterol. 2010; 44: e242-e248
- Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease.Pharmacoepidemiol. Drug Saf. 2004; 13: 563-567
- Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience.Gut. 1993; 34: 1081-1085
- A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia.Nat. Genet. 2014; 46: 1017-1020
- NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease.J. Gastroenterol. 2016; 51: 22-29
- NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD.Pharmacogenomics J. 2016; 16: 280-285
- NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease.Eur. J. Gastroenterol. Hepatol. 2016; 28: 475-478
- Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease.Aliment. Pharmacol. Ther. 2008; 28: 973-983
- Common Terminology Criteria for Adverse Events v4.0.2009
- Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.Nat. Med. 2006; 12: 446-451
- Foxp1 regulates the proliferation of hair follicle stem cells in response to oxidative stress during hair cycling.PLoS One. 2015; 10: e0131674
- Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2.J. Biol. Chem. 2012; 287: 21541-21549
- The Nudix hydrolase superfamily.Cell. Mol. Life Sci. 2006; 63: 123-143
Published online: April 26, 2017
Accepted: April 25, 2017
Received in revised form: April 21, 2017
Received: December 27, 2016
© 2017 Elsevier B.V. All rights reserved.