{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T15:23:35Z","timestamp":1778081015147,"version":"3.51.4"},"reference-count":38,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single\u2010locus analysis showed that the single\u2010nucleotide polymorphisms (SNPs) <jats:italic>RRM1<\/jats:italic> rs12806698 and rs11031918 and <jats:italic>DCTD<\/jats:italic> rs7663494 were significantly associated with severe neutropenia, <jats:italic>hENT1<\/jats:italic> rs760370 and <jats:italic>hCNT3<\/jats:italic> rs7867504 and rs4877831 were associated with severe leukopenia, <jats:italic>CDA<\/jats:italic> rs2072671, <jats:italic>DCTD<\/jats:italic> rs7663494, and <jats:italic>WEE1<\/jats:italic> rs3910384 were associated with severe anemia, and <jats:italic>MTHFR<\/jats:italic> rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (<jats:italic>P<\/jats:italic> &lt; .0038). The gene\u2010gene interaction analysis identified the overall best models, including a 2\u2010way interaction model (<jats:italic>hCNT3<\/jats:italic> rs7867504 and <jats:italic>dCK<\/jats:italic> rs12648166) for severe leukopenia (<jats:italic>P =<\/jats:italic> .0022) and a 3\u2010locus model (<jats:italic>CDA<\/jats:italic> rs207671, <jats:italic>DCTD<\/jats:italic> rs7663494, and <jats:italic>WEE1<\/jats:italic> rs3910384) for severe anemia with a strong synergistic effect (<jats:italic>P =<\/jats:italic> .0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene\u2010gene interaction of gemcitabine metabolic pathway genes and <jats:italic>WEE1<\/jats:italic> contributes to susceptibility to gemcitabine\u2010induced hematological toxicity. Moreover, we propose a promising data\u2010mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene\u2010gene interactions.<\/jats:p>","DOI":"10.1002\/jcph.1909","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T18:37:08Z","timestamp":1620758228000},"page":"1376-1385","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gene\u2010Gene Interactions of Gemcitabine Metabolizing\u2010Enzyme Genes <i>hCNT3<\/i> and <i>WEE1<\/i> for Preventing Severe Gemcitabine\u2010Induced Hematological Toxicity"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8186-2045","authenticated-orcid":false,"given":"Juan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacy Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai People's Republic of 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