{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:07:01Z","timestamp":1791313621762,"version":"4.3.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"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. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Genetic variation in the <jats:italic>thiopurine S-methyltransferase<\/jats:italic> (<jats:italic>TPMT<\/jats:italic>) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in <jats:italic>TPMT<\/jats:italic> still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously.<\/jats:p><jats:p><jats:bold>Objective:<\/jats:bold> The aim of this study was to evaluate the effect of genetic variants in <jats:italic>ITPA<\/jats:italic>, <jats:italic>TPMT<\/jats:italic>, <jats:italic>NUDT15<\/jats:italic>, <jats:italic>XDH<\/jats:italic>, and <jats:italic>ABCB1<\/jats:italic> on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Genotyping of <jats:italic>ITPA<\/jats:italic>, and <jats:italic>XDH<\/jats:italic> was performed using KASP genotyping assay, while that of <jats:italic>TPMT<\/jats:italic>, <jats:italic>NUDT15,<\/jats:italic> and <jats:italic>ABCB1<\/jats:italic> with TaqMan<jats:sup>\u00ae<\/jats:sup> SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> In this study, genetic variants in <jats:italic>XDH<\/jats:italic> and <jats:italic>ITPA<\/jats:italic> were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for <jats:italic>XDH<\/jats:italic> rs2281547 were 2.956 times (AHR\u20092.956, 95% CI = 1.494\u20135.849, <jats:italic>p<\/jats:italic> = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> In conclusion, in this cohort, <jats:italic>XDH<\/jats:italic> rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than <jats:italic>TPMT<\/jats:italic> involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.<\/jats:p>","DOI":"10.3389\/fphar.2023.1159307","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T05:35:46Z","timestamp":1683610546000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia"],"prefix":"10.3389","volume":"14","author":[{"given":"Awol Mekonnen","family":"Ali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haileyesus","family":"Adam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hailu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ephrem","family":"Engidawork","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawleigh","family":"Howe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teferra","family":"Abula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke J. 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