{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T01:32:41Z","timestamp":1778203961921,"version":"3.51.4"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Thiopurines such as 6\u2010mercaptopurine (6MP) are essential in ALL maintenance therapy. However, dose\u2010limiting toxicities can significantly disrupt treatment. While genetic variants in\n                    <jats:italic>TPMT<\/jats:italic>\n                    and\n                    <jats:italic>NUDT15<\/jats:italic>\n                    are known to affect thiopurine response, many patients with normal function genotypes in these genes still experience adverse effects, suggesting that additional genes might be involved. We analyzed 663 pediatric ALL patients enrolled in the AALL03N1 trial to identify novel genetic determinants of 6MP sensitivity, focusing on individuals with normal function\n                    <jats:italic>TPMT<\/jats:italic>\n                    and\n                    <jats:italic>NUDT15<\/jats:italic>\n                    genotypes. A transcriptome\u2010wide association study (TWAS) was conducted to focus on expression quantitative trait loci (eQTLs). Findings were validated in two independent cohorts: St. Jude Total Therapy XV (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009390) and XVI (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009552). TWAS identified 31 genes associated with 6MP dose intensity (\n                    <jats:italic>q<\/jats:italic>\n                    \u2010value\u2009&lt;\u20090.90). Of these, the imputed\n                    <jats:italic>GNAQ<\/jats:italic>\n                    expression was positively correlated with 6MP dose intensity and passed multiple testing thresholds in the validation cohorts. The rs60561071 variant, the eQTL in the\n                    <jats:italic>GNAQ<\/jats:italic>\n                    TWAS model, was associated with reduced gene expression and lower 6MP dose intensity. This study identifies\n                    <jats:italic>GNAQ<\/jats:italic>\n                    as a novel gene associated with thiopurine tolerance in ALL patients lacking known risk alleles in\n                    <jats:italic>TPMT<\/jats:italic>\n                    and\n                    <jats:italic>NUDT15<\/jats:italic>\n                    . Moreover, this research highlighted the innovative use of TWAS, providing deeper insights into the molecular mechanisms that explain drug response variability.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70053","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T07:55:14Z","timestamp":1757058914000},"page":"84-88","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unraveling Novel Genetic Determinants of Thiopurine Response Via\n                    <scp>TWAS<\/scp>"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5756-4750","authenticated-orcid":false,"given":"Carlotta","family":"Bidoli","sequence":"first","affiliation":[{"name":"Department of Life Sciences University of Trieste  Trieste Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-5649","authenticated-orcid":false,"given":"Wenjian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seth E.","family":"Karol","sequence":"additional","affiliation":[{"name":"Department of Oncology St. Jude Children\u2019s Research Hospital  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1355-3782","authenticated-orcid":false,"given":"Marianna","family":"Lucaf\u00f2","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Trieste  Trieste Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Stocco","sequence":"additional","affiliation":[{"name":"Department of Translational and Advanced Diagnostics, Institute for Maternal and Child Health \u2013 IRCCS Burlo Garofolo  Trieste Italy"},{"name":"Department of Medical, Surgical and Health Sciences University of Trieste  Trieste Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun J.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences St. Jude Children\u2019s Research Hospital  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1400972"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e328334338f"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)33018-1"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.5217\/ir.2020.00155"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31821a7c34"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000430"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-420196-5.00010-1"},{"key":"e_1_2_9_8_1","volume-title":"Medical Genetics Summaries","author":"Azathioprine D.L.","year":"2012"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1304"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.4671"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.278411"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","unstructured":"Taliun D.et al.Sequencing of 53 831 diverse genomes from the NHLBI TOPMed Program(2019)https:\/\/doi.org\/10.1101\/563866.","DOI":"10.1101\/563866"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007889"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02112-7"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00267"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14133066"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40291-016-0232-1"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2022.1006027"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092735"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12032-9"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2014.53"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmx024"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.04.015"}],"container-title":["Clinical Pharmacology &amp; 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