NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn’s disease

Lee, Yeoun Joo; Hwang, Eun Ha; Park, Jae Hong; Shin, Jin‐Hong; Kang, Boram; Kim, Sun-Young

doi:10.1097/meg.0000000000000564

Cited by 49 publications

(53 citation statements)

References 10 publications

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“…Importantly, many investigators have been able to replicate these results in studies of thiopurine-treated patients with IBD or ALL 789101112131415161718. In the current study, we successfully established a significant association between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss.…”

Section: Discussionsupporting

confidence: 56%

“…The high specificity and sensitivity (89.4% and 93.2%, respectively) of NUDT15 p.Arg139Cys recorded by these authors indicate that this variant, rather than TPMT polymorphisms, may be an effective genetic marker for predicting thiopurine-induced adverse events, at least in East Asian populations. To date, this strong association has been confirmed in numerous studies involving subjects with IBD or ALL 789101112131415161718. In addition, a further investigation identified 4 NUDT15 coding variants, including p.Arg139Cys, that influence both nucleotide diphosphatase activity and levels of thiopurine active metabolites, and found loss-of-function NUDT15 variants to be associated with thiopurine intolerance 13.…”

Section: Introductionmentioning

confidence: 74%

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NUDT15,FTO, andRUNX1genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

et al. 2017

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Background/AimsRecent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD).MethodsOne hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing.ResultsNone of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined.ConclusionsOf the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 74%

NUDT15,FTO, andRUNX1genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

et al. 2017

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“…The allele frequency for the variant T allele in this patient cohort was 7.5% (9/120). From previous studies, patients carrying one or more of the loss-of-function missense variants were found to have increased risk of developing leukopenia during thiopurine therapy [26]; thus, the eight patients (13.3%) with one or more mutant alleles were identified to have thiopurine intolerance by NUDT15 genotyping. The remaining 52 (86.7%) were homozygous for the wild-type C allele and were unaffected.…”

Section: Resultsmentioning

confidence: 99%

Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C)

Fong

Poon

2017

Diagnostics

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Thiopurine intolerance and treatment-related toxicity, such as fatal myelosuppression, is related to non-function genetic variants encoding thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15). Genetic testing of the common variants NUDT15:NM_018283.2:c.415C>T (Arg139Cys, dbSNP rs116855232 T allele) and TPMT: NM_000367.4:c.719A>G (TPMT*3C, dbSNP rs1142345 G allele) in East Asians including Chinese can potentially prevent treatment-related complications. Two complementary genotyping approaches, real-time PCR-high resolution melt (PCR-HRM) and PCR-restriction fragment length morphism (PCR-RFLP) analysis were evaluated using conventional PCR and Sanger sequencing genotyping as the gold standard. Sixty patient samples were tested, revealing seven patients (11.7%) heterozygous for NUDT15 c.415C>T, one patient homozygous for the variant and one patient heterozygous for the TPMT*3C non-function allele. No patient was found to harbor both variants. In total, nine out of 60 (15%) patients tested had genotypic evidence of thiopurine intolerance, which may require dosage adjustment or alternative medication should they be started on azathioprine, mercaptopurine or thioguanine. The two newly developed assays were more efficient and showed complete concordance (60/60, 100%) compared to the Sanger sequencing results. Accurate and cost-effective genotyping assays by real-time PCR-HRM and PCR-RFLP for NUDT15 c.415C>T and TPMT*3C were successfully developed. Further studies may establish their roles in genotype-informed clinical decision-making in the prevention of morbidity and mortality due to thiopurine intolerance.

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“…However, thiopurine‐induced leukopenia is less associated with TPMT variants in Asian IBD patients . A genome‐wide association study of Korean patients with Crohn's disease revealed that a missense variant in exon 3 of nucleoside diphosphate‐linked moiety X‐type motif 15 ( NUDT15 ) gene (R139C; rs116855232) is associated with thiopurine‐induced leukopenia . Furthermore, Japanese studies have revealed that severe leukopenia and complete hair loss are inevitable in patients with the homozygous variant of NUDT15 R139C (T/T genotype) and demonstrated that patients harboring the heterozygous variant (C/T genotype) experience early leukopenia more frequently than those of the wild‐type genotype (C/C genotype) …”

Section: Introductionmentioning

confidence: 99%

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

Akiyama

Matsuoka

Fukuda

et al. 2019

J of Gastro and Hepatol

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Background and Aim A missense variant of the nucleoside diphosphate‐linked moiety X‐type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine‐induced leukopenia. This study evaluates the long‐term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. Methods We enrolled 83 Japanese IBD patients who were on anti‐tumor necrosis factor‐α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. Results The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2–4 leukopenia by 6 months, which persisted through 12–24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. Conclusions NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

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NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn’s disease

Cited by 49 publications

References 10 publications

NUDT15,FTO, andRUNX1genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

NUDT15,FTO, andRUNX1genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C)

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

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