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A recent genomewide association study has identified germline polymorphisms (e.g., rs72846714) in the\n                    <jats:italic>NT5C2<\/jats:italic>\n                    gene associated with 6\u2010MP metabolism in patients with ALL. However, the full spectrum of genetic variation in\n                    <jats:italic>NT5C2<\/jats:italic>\n                    is unclear and its impact on 6\u2010MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of\n                    <jats:italic>NT5C2<\/jats:italic>\n                    in 588 children with ALL and identified 121 single nucleotide polymorphisms nominally associated with erythrocyte TGN during 6\u2010MP treatment (\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0&lt;\u00a00.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6\u2010MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6\u2010MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated\n                    <jats:italic>NT5C2<\/jats:italic>\n                    transcription in\u2010\n                    <jats:italic>cis<\/jats:italic>\n                    . Our results indicated that\n                    <jats:italic>NT5C2<\/jats:italic>\n                    germline variation significantly contributes to interpatient variability in thiopurine drug disposition.\n                  <\/jats:p>","DOI":"10.1002\/cpt.2095","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T22:21:16Z","timestamp":1604010076000},"page":"1538-1545","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Effects of\n                    <i>NT5C2<\/i>\n                    Germline Variants on 6\u2010Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia"],"prefix":"10.1111","volume":"109","author":[{"given":"Chuang","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Hematology &amp; Oncology Shanghai Children\u2019s Medical Center Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"Department of Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital Memphis Tennessee USA"},{"name":"Department of Hematology\/Oncology Guangzhou Women and Children\u2019s Medical Center Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaya","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengcheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital Memphis Tennessee 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R.","family":"Crews","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology Guangzhou Women and Children\u2019s Medical Center Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching\u2010Hon","family":"Pui","sequence":"additional","affiliation":[{"name":"Department of Oncology St. Jude Children\u2019s Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital Memphis Tennessee 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