Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-11-30

AUTHORS

Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa

ABSTRACT

The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations. Several genes code thiopurine-metabolizing enzymes, including TPMT, multidrug-resistance protein 4, and inosine triphosphatase. These genes have been studied as candidate pharmacogenetic markers; however, it remains unclear why Asian populations seem to be more intolerant than other ethnic groups to a full dose of thiopurines. A genome-wide association approach to identify Asian-specific pharmacogenetic markers in Korean patients with Crohn’s disease revealed that a non-synonymous single nucelotide polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) which causes p.Arg139Cys was strongly associated with thiopurine-induced early leukopenia. Six common haplotypes of NUDT15 were reported, and five variants showed medium-to-low enzyme activities, compared with the wild haplotype. NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia. In clinical application, NUDT15 genotyping is a good candidate for predicting thiopurine toxicity in East Asian populations. However, the association of NUDT15 diplotypes with thiopurine toxicity remains unclear. Further analyses with large cohorts to confirm the clinical effects of each haplotype are planned. More... »

PAGES

172-180

References to SciGraph publications

  • 2003-08. Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis in JOURNAL OF GASTROENTEROLOGY
  • 2004-04. Methylated Metabolites of 6‐mercaptopurine are Associated with Hepatotoxicity in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2015-06-16. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD in THE PHARMACOGENOMICS JOURNAL
  • 2015-11-21. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease in JOURNAL OF GASTROENTEROLOGY
  • 2011-01-26. Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2009-02-13. Thiopurine S-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment in JOURNAL OF GASTROENTEROLOGY
  • 2014-09-01. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia in NATURE GENETICS
  • 2010-04-15. The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease in JOURNAL OF GASTROENTEROLOGY
  • 2015-08-21. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals in NATURE COMMUNICATIONS
  • 2017-05-02. One amino acid makes a difference–Characterization of a new TPMT allele and the influence of SAM on TPMT stability in SCIENTIFIC REPORTS
  • 2011-03-15. Efficacy of Immunosuppressive Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis in THE AMERICAN JOURNAL OF GASTROENTEROLOGY
  • 2017-04-18. Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia in THE PHARMACOGENOMICS JOURNAL
  • 2015-11-26. iJGVD: an integrative Japanese genome variation database based on whole-genome sequencing in HUMAN GENOME VARIATION
  • 2006-05-17. Rapid genotyping of common deficient thiopurine S-methyltransferase alleles using the DNA-microchip technique in EUROPEAN JOURNAL OF HUMAN GENETICS
  • 2015-08-04. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2 in NATURE COMMUNICATIONS
  • 2000-08. Thiopurine methyltransferase polymorphic tandem repeat: Genotype‐phenotype correlation analysis in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2016-02-15. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity in NATURE GENETICS
  • 2015-10-27. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia in THE PHARMACOGENOMICS JOURNAL
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00535-017-1416-0

    DOI

    http://dx.doi.org/10.1007/s00535-017-1416-0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1093094495

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29192347


    Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
    Incoming Citations Browse incoming citations for this publication using opencitations.net

    JSON-LD is the canonical representation for SciGraph data.

    TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

    [
      {
        "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
        "about": [
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Medical and Health Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1115", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Pharmacology and Pharmaceutical Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Asians", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Gastrointestinal Agents", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Genotype", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Humans", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Inflammatory Bowel Diseases", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Mercaptopurine", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Pyrophosphatases", 
            "type": "DefinedTerm"
          }
        ], 
        "author": [
          {
            "affiliation": {
              "alternateName": "Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, 980-8574, Sendai, Japan", 
              "id": "http://www.grid.ac/institutes/grid.69566.3a", 
              "name": [
                "Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, 980-8574, Sendai, Japan"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Kakuta", 
            "givenName": "Yoichi", 
            "id": "sg:person.012611662635.04", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012611662635.04"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Institute for Excellent in Higher Education, Tohoku University, Sendai, Japan", 
              "id": "http://www.grid.ac/institutes/grid.69566.3a", 
              "name": [
                "Institute for Excellent in Higher Education, Tohoku University, Sendai, Japan"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Kinouchi", 
            "givenName": "Yoshitaka", 
            "id": "sg:person.01145574514.32", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01145574514.32"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, 980-8574, Sendai, Japan", 
              "id": "http://www.grid.ac/institutes/grid.69566.3a", 
              "name": [
                "Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, 980-8574, Sendai, Japan"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Shimosegawa", 
            "givenName": "Tooru", 
            "id": "sg:person.01255535707.76", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01255535707.76"
            ], 
            "type": "Person"
          }
        ], 
        "citation": [
          {
            "id": "sg:pub.10.1038/tpj.2015.75", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1014701659", 
              "https://doi.org/10.1038/tpj.2015.75"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/tpj.2015.43", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1047288958", 
              "https://doi.org/10.1038/tpj.2015.43"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ncomms9018", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1029523624", 
              "https://doi.org/10.1038/ncomms9018"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00535-010-0248-y", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001357550", 
              "https://doi.org/10.1007/s00535-010-0248-y"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00535-008-2307-1", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008836843", 
              "https://doi.org/10.1007/s00535-008-2307-1"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/clpt.2010.320", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1036623071", 
              "https://doi.org/10.1038/clpt.2010.320"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.ejhg.5201647", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1038356791", 
              "https://doi.org/10.1038/sj.ejhg.5201647"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ajg.2011.64", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1011946124", 
              "https://doi.org/10.1038/ajg.2011.64"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ng.3508", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1013931386", 
              "https://doi.org/10.1038/ng.3508"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ncomms8871", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1002261592", 
              "https://doi.org/10.1038/ncomms8871"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1067/mcp.2000.108674", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1005506858", 
              "https://doi.org/10.1067/mcp.2000.108674"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ng.3060", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1051527727", 
              "https://doi.org/10.1038/ng.3060"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00535-015-1142-4", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1031497620", 
              "https://doi.org/10.1007/s00535-015-1142-4"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/hgv.2015.50", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1046472396", 
              "https://doi.org/10.1038/hgv.2015.50"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/srep46428", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1084956127", 
              "https://doi.org/10.1038/srep46428"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1016/j.clpt.2003.12.001", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1039519767", 
              "https://doi.org/10.1016/j.clpt.2003.12.001"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/tpj.2017.12", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1084904738", 
              "https://doi.org/10.1038/tpj.2017.12"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00535-003-1139-2", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1052421926", 
              "https://doi.org/10.1007/s00535-003-1139-2"
            ], 
            "type": "CreativeWork"
          }
        ], 
        "datePublished": "2017-11-30", 
        "datePublishedReg": "2017-11-30", 
        "description": "The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations. Several genes code thiopurine-metabolizing enzymes, including TPMT, multidrug-resistance protein 4, and inosine triphosphatase. These genes have been studied as candidate pharmacogenetic markers; however, it remains unclear why Asian populations seem to be more intolerant than other ethnic groups to a full dose of thiopurines. A genome-wide association approach to identify Asian-specific pharmacogenetic markers in Korean patients with Crohn\u2019s disease revealed that a non-synonymous single nucelotide polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) which causes p.Arg139Cys was strongly associated with thiopurine-induced early leukopenia. Six common haplotypes of NUDT15 were reported, and five variants showed medium-to-low enzyme activities, compared with the wild haplotype. NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia. In clinical application, NUDT15 genotyping is a good candidate for predicting thiopurine toxicity in East Asian populations. However, the association of NUDT15 diplotypes with thiopurine toxicity remains unclear. Further analyses with large cohorts to confirm the clinical effects of each haplotype are planned.", 
        "genre": "article", 
        "id": "sg:pub.10.1007/s00535-017-1416-0", 
        "inLanguage": "en", 
        "isAccessibleForFree": true, 
        "isPartOf": [
          {
            "id": "sg:journal.1009747", 
            "issn": [
              "0944-1174", 
              "1435-5922"
            ], 
            "name": "Journal of Gastroenterology", 
            "publisher": "Springer Nature", 
            "type": "Periodical"
          }, 
          {
            "issueNumber": "2", 
            "type": "PublicationIssue"
          }, 
          {
            "type": "PublicationVolume", 
            "volumeNumber": "53"
          }
        ], 
        "keywords": [
          "low enzyme activity", 
          "thiopurine S-methyltransferase", 
          "wide association approach", 
          "East Asian populations", 
          "enzyme activity", 
          "multidrug resistance protein 4", 
          "single nucelotide polymorphisms", 
          "candidate pharmacogenetic markers", 
          "mechanisms of toxicity", 
          "wild haplotype", 
          "association approach", 
          "genetic variants", 
          "thiopurine toxicity", 
          "common haplotype", 
          "protein 4", 
          "haplotypes", 
          "genes", 
          "S-methyltransferase", 
          "enzyme", 
          "Asian populations", 
          "variants", 
          "genotyping", 
          "methylation", 
          "Further analysis", 
          "pharmacogenetic markers", 
          "GTP", 
          "population", 
          "metabolites", 
          "markers", 
          "dGTP", 
          "high levels", 
          "polymorphism", 
          "toxicity", 
          "East Asia", 
          "triphosphatase", 
          "activity", 
          "active metabolite", 
          "clinical application", 
          "diplotypes", 
          "Asia", 
          "disease", 
          "mechanism", 
          "good candidate", 
          "modification", 
          "NUDT15", 
          "pharmacogenetics", 
          "inflammatory bowel disease", 
          "NUDT15 genotyping", 
          "pharmacogenetic predictors", 
          "levels", 
          "individuals", 
          "bowel disease", 
          "candidates", 
          "medium", 
          "association", 
          "analysis", 
          "effect", 
          "early leukopenia", 
          "large cohort", 
          "azathiopurine", 
          "prospects", 
          "thiopurines", 
          "group", 
          "Crohn's disease", 
          "reaction", 
          "full dose", 
          "approach", 
          "applications", 
          "ethnic groups", 
          "Korean patients", 
          "clinical setting", 
          "adverse reactions", 
          "clinical effects", 
          "treatment modification", 
          "drug doses", 
          "doses", 
          "leukopenia", 
          "Western countries", 
          "cohort", 
          "dose", 
          "incidence", 
          "predictors", 
          "patients", 
          "countries", 
          "setting"
        ], 
        "name": "Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping", 
        "pagination": "172-180", 
        "productId": [
          {
            "name": "dimensions_id", 
            "type": "PropertyValue", 
            "value": [
              "pub.1093094495"
            ]
          }, 
          {
            "name": "doi", 
            "type": "PropertyValue", 
            "value": [
              "10.1007/s00535-017-1416-0"
            ]
          }, 
          {
            "name": "pubmed_id", 
            "type": "PropertyValue", 
            "value": [
              "29192347"
            ]
          }
        ], 
        "sameAs": [
          "https://doi.org/10.1007/s00535-017-1416-0", 
          "https://app.dimensions.ai/details/publication/pub.1093094495"
        ], 
        "sdDataset": "articles", 
        "sdDatePublished": "2022-05-20T07:33", 
        "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
        "sdPublisher": {
          "name": "Springer Nature - SN SciGraph project", 
          "type": "Organization"
        }, 
        "sdSource": "s3://com-springernature-scigraph/baseset/20220519/entities/gbq_results/article/article_731.jsonl", 
        "type": "ScholarlyArticle", 
        "url": "https://doi.org/10.1007/s00535-017-1416-0"
      }
    ]
     

    Download the RDF metadata as:  json-ld nt turtle xml License info

    HOW TO GET THIS DATA PROGRAMMATICALLY:

    JSON-LD is a popular format for linked data which is fully compatible with JSON.

    curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1007/s00535-017-1416-0'

    N-Triples is a line-based linked data format ideal for batch operations.

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1007/s00535-017-1416-0'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1007/s00535-017-1416-0'

    RDF/XML is a standard XML format for linked data.

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1007/s00535-017-1416-0'


     

    This table displays all metadata directly associated to this object as RDF triples.

    263 TRIPLES      22 PREDICATES      136 URIs      110 LITERALS      14 BLANK NODES

    Subject Predicate Object
    1 sg:pub.10.1007/s00535-017-1416-0 schema:about N1c0a146d5156459aab5d8c0b97a1b9ab
    2 N36f2c85d068447aeac933889967aeca3
    3 N75cb32fc5c39427b96db52332bab04bf
    4 N76972fb43b3c45e1b31b11bfd366cd20
    5 Na2385de41c6344379fab633bef8d4911
    6 Na83b4eb142784224b67c6573e69c6266
    7 Nec01462802874e6b809eee0143e6bbc2
    8 anzsrc-for:11
    9 anzsrc-for:1115
    10 schema:author Ne994b61b3cb64f9e8fabb1b9f03c4abd
    11 schema:citation sg:pub.10.1007/s00535-003-1139-2
    12 sg:pub.10.1007/s00535-008-2307-1
    13 sg:pub.10.1007/s00535-010-0248-y
    14 sg:pub.10.1007/s00535-015-1142-4
    15 sg:pub.10.1016/j.clpt.2003.12.001
    16 sg:pub.10.1038/ajg.2011.64
    17 sg:pub.10.1038/clpt.2010.320
    18 sg:pub.10.1038/hgv.2015.50
    19 sg:pub.10.1038/ncomms8871
    20 sg:pub.10.1038/ncomms9018
    21 sg:pub.10.1038/ng.3060
    22 sg:pub.10.1038/ng.3508
    23 sg:pub.10.1038/sj.ejhg.5201647
    24 sg:pub.10.1038/srep46428
    25 sg:pub.10.1038/tpj.2015.43
    26 sg:pub.10.1038/tpj.2015.75
    27 sg:pub.10.1038/tpj.2017.12
    28 sg:pub.10.1067/mcp.2000.108674
    29 schema:datePublished 2017-11-30
    30 schema:datePublishedReg 2017-11-30
    31 schema:description The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations. Several genes code thiopurine-metabolizing enzymes, including TPMT, multidrug-resistance protein 4, and inosine triphosphatase. These genes have been studied as candidate pharmacogenetic markers; however, it remains unclear why Asian populations seem to be more intolerant than other ethnic groups to a full dose of thiopurines. A genome-wide association approach to identify Asian-specific pharmacogenetic markers in Korean patients with Crohn’s disease revealed that a non-synonymous single nucelotide polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) which causes p.Arg139Cys was strongly associated with thiopurine-induced early leukopenia. Six common haplotypes of NUDT15 were reported, and five variants showed medium-to-low enzyme activities, compared with the wild haplotype. NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia. In clinical application, NUDT15 genotyping is a good candidate for predicting thiopurine toxicity in East Asian populations. However, the association of NUDT15 diplotypes with thiopurine toxicity remains unclear. Further analyses with large cohorts to confirm the clinical effects of each haplotype are planned.
    32 schema:genre article
    33 schema:inLanguage en
    34 schema:isAccessibleForFree true
    35 schema:isPartOf Nd3eecc4a1c8446a9800441f35370c058
    36 Nddac9680e79e4a6faa534dff0784a204
    37 sg:journal.1009747
    38 schema:keywords Asia
    39 Asian populations
    40 Crohn's disease
    41 East Asia
    42 East Asian populations
    43 Further analysis
    44 GTP
    45 Korean patients
    46 NUDT15
    47 NUDT15 genotyping
    48 S-methyltransferase
    49 Western countries
    50 active metabolite
    51 activity
    52 adverse reactions
    53 analysis
    54 applications
    55 approach
    56 association
    57 association approach
    58 azathiopurine
    59 bowel disease
    60 candidate pharmacogenetic markers
    61 candidates
    62 clinical application
    63 clinical effects
    64 clinical setting
    65 cohort
    66 common haplotype
    67 countries
    68 dGTP
    69 diplotypes
    70 disease
    71 dose
    72 doses
    73 drug doses
    74 early leukopenia
    75 effect
    76 enzyme
    77 enzyme activity
    78 ethnic groups
    79 full dose
    80 genes
    81 genetic variants
    82 genotyping
    83 good candidate
    84 group
    85 haplotypes
    86 high levels
    87 incidence
    88 individuals
    89 inflammatory bowel disease
    90 large cohort
    91 leukopenia
    92 levels
    93 low enzyme activity
    94 markers
    95 mechanism
    96 mechanisms of toxicity
    97 medium
    98 metabolites
    99 methylation
    100 modification
    101 multidrug resistance protein 4
    102 patients
    103 pharmacogenetic markers
    104 pharmacogenetic predictors
    105 pharmacogenetics
    106 polymorphism
    107 population
    108 predictors
    109 prospects
    110 protein 4
    111 reaction
    112 setting
    113 single nucelotide polymorphisms
    114 thiopurine S-methyltransferase
    115 thiopurine toxicity
    116 thiopurines
    117 toxicity
    118 treatment modification
    119 triphosphatase
    120 variants
    121 wide association approach
    122 wild haplotype
    123 schema:name Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping
    124 schema:pagination 172-180
    125 schema:productId N5792d196911443d085608015f0168432
    126 N68a6e2949385409a8a8d27ab30e1d0d0
    127 N74b895aaf8a54feea2d4453b65085970
    128 schema:sameAs https://app.dimensions.ai/details/publication/pub.1093094495
    129 https://doi.org/10.1007/s00535-017-1416-0
    130 schema:sdDatePublished 2022-05-20T07:33
    131 schema:sdLicense https://scigraph.springernature.com/explorer/license/
    132 schema:sdPublisher N7a36b119259444559750a298d7695059
    133 schema:url https://doi.org/10.1007/s00535-017-1416-0
    134 sgo:license sg:explorer/license/
    135 sgo:sdDataset articles
    136 rdf:type schema:ScholarlyArticle
    137 N1c0a146d5156459aab5d8c0b97a1b9ab schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    138 schema:name Mercaptopurine
    139 rdf:type schema:DefinedTerm
    140 N36f2c85d068447aeac933889967aeca3 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    141 schema:name Asians
    142 rdf:type schema:DefinedTerm
    143 N5792d196911443d085608015f0168432 schema:name dimensions_id
    144 schema:value pub.1093094495
    145 rdf:type schema:PropertyValue
    146 N68a6e2949385409a8a8d27ab30e1d0d0 schema:name doi
    147 schema:value 10.1007/s00535-017-1416-0
    148 rdf:type schema:PropertyValue
    149 N74b895aaf8a54feea2d4453b65085970 schema:name pubmed_id
    150 schema:value 29192347
    151 rdf:type schema:PropertyValue
    152 N75cb32fc5c39427b96db52332bab04bf schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    153 schema:name Inflammatory Bowel Diseases
    154 rdf:type schema:DefinedTerm
    155 N76972fb43b3c45e1b31b11bfd366cd20 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    156 schema:name Gastrointestinal Agents
    157 rdf:type schema:DefinedTerm
    158 N7a36b119259444559750a298d7695059 schema:name Springer Nature - SN SciGraph project
    159 rdf:type schema:Organization
    160 Na10f5a645286485ab51eb5b35384e205 rdf:first sg:person.01145574514.32
    161 rdf:rest Nd55d1ef81bcd4f7abeda268c9f3a376f
    162 Na2385de41c6344379fab633bef8d4911 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    163 schema:name Genotype
    164 rdf:type schema:DefinedTerm
    165 Na83b4eb142784224b67c6573e69c6266 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    166 schema:name Pyrophosphatases
    167 rdf:type schema:DefinedTerm
    168 Nd3eecc4a1c8446a9800441f35370c058 schema:volumeNumber 53
    169 rdf:type schema:PublicationVolume
    170 Nd55d1ef81bcd4f7abeda268c9f3a376f rdf:first sg:person.01255535707.76
    171 rdf:rest rdf:nil
    172 Nddac9680e79e4a6faa534dff0784a204 schema:issueNumber 2
    173 rdf:type schema:PublicationIssue
    174 Ne994b61b3cb64f9e8fabb1b9f03c4abd rdf:first sg:person.012611662635.04
    175 rdf:rest Na10f5a645286485ab51eb5b35384e205
    176 Nec01462802874e6b809eee0143e6bbc2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    177 schema:name Humans
    178 rdf:type schema:DefinedTerm
    179 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
    180 schema:name Medical and Health Sciences
    181 rdf:type schema:DefinedTerm
    182 anzsrc-for:1115 schema:inDefinedTermSet anzsrc-for:
    183 schema:name Pharmacology and Pharmaceutical Sciences
    184 rdf:type schema:DefinedTerm
    185 sg:journal.1009747 schema:issn 0944-1174
    186 1435-5922
    187 schema:name Journal of Gastroenterology
    188 schema:publisher Springer Nature
    189 rdf:type schema:Periodical
    190 sg:person.01145574514.32 schema:affiliation grid-institutes:grid.69566.3a
    191 schema:familyName Kinouchi
    192 schema:givenName Yoshitaka
    193 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01145574514.32
    194 rdf:type schema:Person
    195 sg:person.01255535707.76 schema:affiliation grid-institutes:grid.69566.3a
    196 schema:familyName Shimosegawa
    197 schema:givenName Tooru
    198 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01255535707.76
    199 rdf:type schema:Person
    200 sg:person.012611662635.04 schema:affiliation grid-institutes:grid.69566.3a
    201 schema:familyName Kakuta
    202 schema:givenName Yoichi
    203 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012611662635.04
    204 rdf:type schema:Person
    205 sg:pub.10.1007/s00535-003-1139-2 schema:sameAs https://app.dimensions.ai/details/publication/pub.1052421926
    206 https://doi.org/10.1007/s00535-003-1139-2
    207 rdf:type schema:CreativeWork
    208 sg:pub.10.1007/s00535-008-2307-1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008836843
    209 https://doi.org/10.1007/s00535-008-2307-1
    210 rdf:type schema:CreativeWork
    211 sg:pub.10.1007/s00535-010-0248-y schema:sameAs https://app.dimensions.ai/details/publication/pub.1001357550
    212 https://doi.org/10.1007/s00535-010-0248-y
    213 rdf:type schema:CreativeWork
    214 sg:pub.10.1007/s00535-015-1142-4 schema:sameAs https://app.dimensions.ai/details/publication/pub.1031497620
    215 https://doi.org/10.1007/s00535-015-1142-4
    216 rdf:type schema:CreativeWork
    217 sg:pub.10.1016/j.clpt.2003.12.001 schema:sameAs https://app.dimensions.ai/details/publication/pub.1039519767
    218 https://doi.org/10.1016/j.clpt.2003.12.001
    219 rdf:type schema:CreativeWork
    220 sg:pub.10.1038/ajg.2011.64 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011946124
    221 https://doi.org/10.1038/ajg.2011.64
    222 rdf:type schema:CreativeWork
    223 sg:pub.10.1038/clpt.2010.320 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036623071
    224 https://doi.org/10.1038/clpt.2010.320
    225 rdf:type schema:CreativeWork
    226 sg:pub.10.1038/hgv.2015.50 schema:sameAs https://app.dimensions.ai/details/publication/pub.1046472396
    227 https://doi.org/10.1038/hgv.2015.50
    228 rdf:type schema:CreativeWork
    229 sg:pub.10.1038/ncomms8871 schema:sameAs https://app.dimensions.ai/details/publication/pub.1002261592
    230 https://doi.org/10.1038/ncomms8871
    231 rdf:type schema:CreativeWork
    232 sg:pub.10.1038/ncomms9018 schema:sameAs https://app.dimensions.ai/details/publication/pub.1029523624
    233 https://doi.org/10.1038/ncomms9018
    234 rdf:type schema:CreativeWork
    235 sg:pub.10.1038/ng.3060 schema:sameAs https://app.dimensions.ai/details/publication/pub.1051527727
    236 https://doi.org/10.1038/ng.3060
    237 rdf:type schema:CreativeWork
    238 sg:pub.10.1038/ng.3508 schema:sameAs https://app.dimensions.ai/details/publication/pub.1013931386
    239 https://doi.org/10.1038/ng.3508
    240 rdf:type schema:CreativeWork
    241 sg:pub.10.1038/sj.ejhg.5201647 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038356791
    242 https://doi.org/10.1038/sj.ejhg.5201647
    243 rdf:type schema:CreativeWork
    244 sg:pub.10.1038/srep46428 schema:sameAs https://app.dimensions.ai/details/publication/pub.1084956127
    245 https://doi.org/10.1038/srep46428
    246 rdf:type schema:CreativeWork
    247 sg:pub.10.1038/tpj.2015.43 schema:sameAs https://app.dimensions.ai/details/publication/pub.1047288958
    248 https://doi.org/10.1038/tpj.2015.43
    249 rdf:type schema:CreativeWork
    250 sg:pub.10.1038/tpj.2015.75 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014701659
    251 https://doi.org/10.1038/tpj.2015.75
    252 rdf:type schema:CreativeWork
    253 sg:pub.10.1038/tpj.2017.12 schema:sameAs https://app.dimensions.ai/details/publication/pub.1084904738
    254 https://doi.org/10.1038/tpj.2017.12
    255 rdf:type schema:CreativeWork
    256 sg:pub.10.1067/mcp.2000.108674 schema:sameAs https://app.dimensions.ai/details/publication/pub.1005506858
    257 https://doi.org/10.1067/mcp.2000.108674
    258 rdf:type schema:CreativeWork
    259 grid-institutes:grid.69566.3a schema:alternateName Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, 980-8574, Sendai, Japan
    260 Institute for Excellent in Higher Education, Tohoku University, Sendai, Japan
    261 schema:name Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, 980-8574, Sendai, Japan
    262 Institute for Excellent in Higher Education, Tohoku University, Sendai, Japan
    263 rdf:type schema:Organization
     




    Preview window. Press ESC to close (or click here)


    ...