{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T20:46:32Z","timestamp":1793047592668,"version":"4.5.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Thiopurines, azathiopurine (AZA) and mercaptopurine (6-MP) have been regularly used in the treatment of inflammatory bowel disease (IBD). Despite optimized dosage adjustment based on the NUDT15 genotypes, some patients still discontinue or change treatment regimens due to thiopurine-induced leukopenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We proposed a prospective observational study of lipidomics to reveal the lipids perturbations associated with thiopurine-induced leukopenia. One hundred and twenty-seven IBD participants treated with thiopurine were enrolled, twenty-seven of which have developed thiopurine-induced leucopenia. Plasma lipid profiles were measured using Ultra-High-Performance Liquid Chromatography-Tandem Q-Exactive. Lipidomic alterations were validated with an independent validation cohort (leukopenia <jats:italic>n<\/jats:italic> = 26, non-leukopenia <jats:italic>n<\/jats:italic> = 74).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using univariate and multivariate analysis, there were 16 lipid species from four lipid classes, triglyceride (<jats:italic>n<\/jats:italic> = 11), sphingomyelin (<jats:italic>n<\/jats:italic> = 1), phosphatidylcholine (<jats:italic>n<\/jats:italic> = 1) and lactosylceramide (<jats:italic>n<\/jats:italic> = 3) identified. Based on machine learning feature reduction and variable screening strategies, the random forest algorithm established by six lipids showed an excellent performance to distinguish the leukopenia group from the normal group, with a model accuracy of 95.28% (discovery cohort), 79.00% (validation cohort) and an area under the receiver operating characteristic (ROC) curve (ROC-AUC) of 0.9989 (discovery cohort), 0.8098 (validation cohort).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our novel findings suggested that lipidomic provided unique insights into formulating individualized medication strategies for thiopurines in IBD patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnut.2023.1138506","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T05:28:01Z","timestamp":1687843681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Plasma lipidomic profiling of thiopurine-induced leukopenia after NUDT15 genotype-guided dosing in Chinese IBD patients"],"prefix":"10.3389","volume":"10","author":[{"given":"Pan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Chao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanhua","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinjin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueding","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1016\/j.immuni.2021.07.004","article-title":"Multiomics analyses reveal a critical role of selenium in controlling t cell differentiation in crohn's disease","volume":"54","author":"Huang","year":"2021","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.1016\/S0140-6736(17)32448-0","article-title":"Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies","volume":"390","author":"Ng","year":"2017","journal-title":"Lancet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"17562848211059954","DOI":"10.1177\/17562848211059954","article-title":"Tumour necrosis factor inhibitors in inflammatory bowel disease: the story continues","volume":"14","author":"Peyrin-Biroulet","year":"2021","journal-title":"Therap Adv Gastroenterol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"105358","DOI":"10.1016\/j.phrs.2020.105358","article-title":"Berberine improves colitis by triggering ahr activation by microbial tryptophan catabolites","volume":"164","author":"Jing","year":"2020","journal-title":"Pharmacol Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1111\/apt.16600","article-title":"Randomised clinical trial: dose optimising strategy by nudt15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease","volume":"54","author":"Chao","year":"2021","journal-title":"Aliment Pharmacol Ther."},{"key":"B6","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/s00535-018-1439-1","article-title":"Evidence-based clinical practice guidelines for inflammatory bowel disease","volume":"53","author":"Matsuoka","year":"2018","journal-title":"J Gastroenterol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/ajg.2018.27","article-title":"Acg clinical guideline: management of crohn's disease in adults","volume":"113","author":"Lichtenstein","year":"2018","journal-title":"Am J Gastroenterol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1093\/ecco-jcc\/jjx181","article-title":"Thiopurines in inflammatory bowel disease: new findings and perspectives","volume":"12","author":"de Boer","year":"2018","journal-title":"J Crohn's Colitis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1136\/gut.50.4.485","article-title":"The Efficacy of Azathioprine for the Treatment of Inflammatory Bowel Disease: A 30 Year Review","volume":"50","author":"Fraser","year":"2002","journal-title":"Gut."},{"key":"B10","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1111\/apt.13559","article-title":"Review Article: Recent Advances in Pharmacogenetics and Pharmacokinetics for Safe and Effective Thiopurine Therapy In inflammatory Bowel Disease","volume":"43","author":"Moon","year":"2016","journal-title":"Aliment Pharmacol Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"5850","DOI":"10.3748\/wjg.v25.i38.5850","article-title":"Nucleoside Diphosphate-Linked Moiety X-Type Motif 15 R139c Genotypes Impact 6-Thioguanine Nucleotide Cut-Off Levels to Predict Thiopurine-Induced Leukopenia in Crohn's Disease Patients","volume":"25","author":"Zhu","year":"2019","journal-title":"World J Gastroenterol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1111\/jgh.15185","article-title":"Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology Practice Recommendations for Medical Management and Monitoring of Inflammatory Bowel Disease in Asia","volume":"36","author":"Ran","year":"2021","journal-title":"J Gastroenterol Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1002\/cpt.1304","article-title":"Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on Tpmt and Nudt15 Genotypes: 2018 Update","volume":"105","author":"Relling","year":"2019","journal-title":"Clin Pharmacol Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1097\/FTD.0b013e3182731925","article-title":"Should thiopurine methyltransferase genotypes and phenotypes be measured before thiopurine therapy in patients with inflammatory bowel disease?","volume":"34","author":"Fangbin","year":"2012","journal-title":"Ther Drug Monit."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3665","DOI":"10.3760\/cma.j.issn.0366-6999.2012.20.012","article-title":"Thiopurine methyltransferase gene polymorphisms and activity in chinese patients with inflammatory bowel disease treated with azathioprine","volume":"125","author":"Zhu","year":"2012","journal-title":"Chin Med J (Engl)."},{"key":"B16","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1111\/apt.13796","article-title":"Nudt15 polymorphisms are better than thiopurine s-methyltransferase as predictor of risk for thiopurine-induced leukopenia in chinese patients with Crohn's disease","volume":"44","author":"Zhu","year":"2016","journal-title":"Aliment Pharmacol Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1200\/JCO.2014.59.4671","article-title":"Inherited Nudt15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia","volume":"33","author":"Yang","year":"2015","journal-title":"J Clin Oncol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/ng.3508","article-title":"Nudt15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity","volume":"48","author":"Moriyama","year":"2016","journal-title":"Nat Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/tpj.2015.43","article-title":"Nudt15 R139c Causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with Ibd","volume":"16","author":"Kakuta","year":"2016","journal-title":"Pharmacogenomics J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.trac.2019.01.009","article-title":"Recent developments and applications of solid phase microextraction as a sample preparation approach for mass-spectrometry-based metabolomics and lipidomics","volume":"113","author":"Reyes-Garces","year":"2019","journal-title":"Trac-Trends Analyt Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"602","DOI":"10.3389\/fphar.2017.00602","volume":"8","author":"Xu","year":"2017","journal-title":"Front Pharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e0255240","DOI":"10.1371\/journal.pone.0255240","article-title":"Utilizing machine learning with knockoff filtering to extract significant metabolites in crohn's disease with a publicly available untargeted metabolomics dataset","volume":"16","author":"Bin Masud","year":"2021","journal-title":"PLoS ONE."},{"key":"B23","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1021\/acs.jproteome.9b00440","article-title":"Uplc-Qtof-Ms-based plasma lipidomic profiling reveals biomarkers for inflammatory bowel disease diagnosis","volume":"19","author":"Guan","year":"2020","journal-title":"J Proteome Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1007\/s11306-018-1439-4","article-title":"Italian cohort of patients affected by inflammatory bowel disease is characterised by variation in glycerophospholipid, free fatty acids and amino acid levels","volume":"14","author":"Murgia","year":"2018","journal-title":"Metabolomics."},{"key":"B25","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/S0022-2275(20)40020-3","article-title":"Cholesterol, phospholipids, and fatty acids of normal immature neutrophils: comparison with acute myeloblastic leukemia cells and normal neutrophils","volume":"20","author":"Klock","year":"1979","journal-title":"J Lipid Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.bbacli.2017.03.002","article-title":"The plasma lipidome in acute myeloid leukemia at diagnosis in relation to clinical disease features","volume":"7","author":"Pabst","year":"2017","journal-title":"BBA Clin."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e0168781","DOI":"10.1371\/journal.pone.0168781","article-title":"Lipidomic approach for stratification of acute myeloid leukemia patients","volume":"12","author":"Stefanko","year":"2017","journal-title":"PLoS ONE."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.3324\/haematol.2021.280147","article-title":"Interplay between hypertriglyceridemia and acute promyelocytic leukemia mediated by the cooperation of peroxisome proliferator-activated receptor-\u03b1 with the PML\/RAR \u03b1 fusion protein on super-enhancers","volume":"107","author":"Wu","year":"2022","journal-title":"Haematologica."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1016\/j.apsb.2022.09.006","article-title":"The role of phosphatidylcholine 34:1 in the occurrence, development and treatment of ulcerative colitis","volume":"13","author":"Yu","year":"2022","journal-title":"Acta Pharmaceutica Sinica B."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1182\/blood.2021013097","article-title":"Platelet Ackr3\/Cxcr7 favors antiplatelet lipids over an atherothrombotic lipidome and regulates thromboinflammation","volume":"139","author":"Cebo","year":"2022","journal-title":"Blood."},{"key":"B31","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1093\/ecco-jcc\/jjaa227","article-title":"Metabolomic analysis in inflammatory bowel disease: a systematic review","volume":"15","author":"Gallagher","year":"2020","journal-title":"J Crohn's Colitis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"5349","DOI":"10.1007\/s00216-017-0483-7","article-title":"Optimization of lipid extraction and analytical protocols for UHPLC-ESI-HRMS-based lipidomic analysis of adherent mammalian cancer cells","volume":"409","author":"Zhang","year":"2017","journal-title":"Anal Bioanal Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3590","DOI":"10.1021\/acs.analchem.8b05592","article-title":"Systematic error removal using random forest for normalizing large-scale untargeted lipidomics data","volume":"91","author":"Fan","year":"2019","journal-title":"Anal Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"180","DOI":"10.2174\/2213235X11301020005","article-title":"Muma, an R package for metabolomics univariate and multivariate statistical analysis","volume":"1","author":"Gaude","year":"2013","journal-title":"Current Metabolomics."},{"key":"B35","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s11306-013-0598-6","article-title":"Reflections on univariate and multivariate analysis of metabolomics data","volume":"10","author":"Saccenti","year":"2014","journal-title":"Metabolomics."},{"key":"B36","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1182\/blood-2002-03-0718","article-title":"Glycosphingolipid expression in acute nonlymphocytic leukemia: common expression of shiga toxin and parvovirus B19 receptors on early myeloblasts","volume":"101","author":"Cooling","year":"2003","journal-title":"Blood."},{"key":"B37","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.bbalip.2014.06.009","article-title":"Organization and functions of glycolipid-enriched microdomains in phagocytes","volume":"1851","author":"Ekyalongo","year":"2015","journal-title":"Biochim Biophys Acta."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.4049\/jimmunol.134.4.2498","article-title":"Glycolipid antigens of human polymorphonuclear neutrophils and the inducible Hl-60 myeloid leukemia line","volume":"134","author":"Symington","year":"1985","journal-title":"J Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1182\/blood.V100.4.1454.h81602001454_1454_1464","article-title":"Lactosylceramide-enriched glycosphingolipid signaling domain mediates superoxide generation from human neutrophils","volume":"100","author":"Iwabuchi","year":"2002","journal-title":"Blood."},{"key":"B40","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s40164-022-00309-7","article-title":"Association between abnormal lipid profile and inflammation and progression of myelodysplastic syndrome to acute leukemia","volume":"11","author":"Qiao","year":"2022","journal-title":"Exp Hematol Oncol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"5050","DOI":"10.3390\/ijms21145050","article-title":"Gemfibrozil induces anemia, leukopenia and reduces hematopoietic stem cells via ppar-\u03b1 in mice","volume":"21","author":"Estrela","year":"2020","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1138506\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T05:28:07Z","timestamp":1687843687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1138506\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":41,"alternative-id":["10.3389\/fnut.2023.1138506"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2023.1138506","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,27]]},"article-number":"1138506"}}