NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease

Asada, Ayumi; Nishida, Atsushi; Shioya, Makoto; Imaeda, Hirotsugu; Inatomi, Osamu; Bamba, Shigeki; Kiura, Katsuyuki; Sugimoto, Mitsushige; Andoh, Akira

doi:10.1007/s00535-015-1142-4

Cited by 89 publications

(143 citation statements)

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“…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%

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: Introductionmentioning

confidence: 74%

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

et al. 2017

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“…More recently, a missense variant NUDT15 gene mutation has been found to confer increased susceptibility to thiopurine-induced leukopenia independently of the 6-thioguanine mechanism in East Asians, specifically studied in Koreans, Japanese, and Taiwanese populations [15,16,17,18] . We had a very low Asian population, and the fact that the NUDT15 mutation is rare in IBD patients of European descent, may explain the extremely low incidence of leukopenia in our study.…”

Section: Discussionmentioning

confidence: 99%

Lymphopenia in Inflammatory Bowel Disease Patients on Immunosuppressive Medications

Abraham

Sellin

2016

Journal of Gastroenterology and Hepatology Research

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Azathioprine and 6-mercaptopurine (AZA/6MP) are effective immunosuppressives used for the treatment of inflammatory bowel disease. The optimal strategy for monitoring therapeutic efficacy and adequate immunosuppression remains to be defined. White blood cell count, mean corpuscle volume (MCV), and 6-mercaptopurine metabolites (6TGN, 6MMP) have all been suggested as potential parameters to monitor efficacy and safety. However, immunomodulators target lymphocytes specifically rather than leukocytes overall; little data is available on the relationship between lymphocytes and immunomodulators in IBD. This study evaluates the incidence of lymphopenia with immunosuppressive use, and correlates metabolite levels (6TGN and 6MMP) with leukocyte, lymphocyte, and MCV levels in IBD patients treated with AZA/6MP. Medical records of 125 adult IBD patients were analyzed based on the use of AZA/6MP, blood counts, and mercaptopurine metabolites 6TGN and 6MMP. Forty three percent of patients taking AZA/6MP developed lymphopenia. Of those with lymphopenia, only 11% had leukopenia. A low but statistically significant correlation of r = -0.3 (p=0.04) for 6TGN to leukocyte counts as well as to MCV levels was found. No correlation between 6TGN levels and lymphocyte counts was noted. This analysis shows that not only leukocyte counts but lymphocyte counts should be monitored closely in patients on these immunosuppressives. Metabolite markers do not provide information regarding who will develop lymphopenia. Consequences of lymphopenia such as opportunistic infections need to be discussed with patients prior to starting this type of therapy.

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“…158 This SNP is rare in European ancestry individuals but is also associated with thiopurine-induced leukopenia in Europeans and the association with bone marrow toxicity has also been reproduced in Japanese IBD patients. 158,161,162 Pancreatitis is one of the dose-independent adverse reactions related with thiopurines limiting their use in IBD. 157 In a recent worldwide study to identify genetic markers predicting pancreatitis within 3 months of starting thiopurines in patients with IBD, a GWAS on 172 cases and 2035 controls as well as additional validation was performed.…”

Section: Pharmacogenetics Associated With Ibd Therapymentioning

confidence: 99%

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

McGovern

2016

Expert Review of Clinical Immunology

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Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD.

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NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease

Abstract: These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism.

Cited by 89 publications

References 29 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

Lymphopenia in Inflammatory Bowel Disease Patients on Immunosuppressive Medications

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

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