Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
J Clin Pharmacol. 2021 Oct;61(10):1376-1385. doi: 10.1002/jcph.1909. Epub 2021 Jun 10.
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-locus analysis showed that the single-nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P < .0038). The gene-gene interaction analysis identified the overall best models, including a 2-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P = .0022) and a 3-locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = .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-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we propose a promising data-mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene-gene interactions.
大多数接受吉西他滨治疗的患者都会经历严重的血液学毒性；因此，预防这种毒性会提高治疗效果和患者的生活质量。我们分析了 132 名接受吉西他滨治疗的患者中转运体、代谢酶、靶标和 DNA 损伤及叶酸途径相关基因中的 13 个多态性，研究了它们与血液学毒性严重程度的关系。单基因分析显示，单核苷酸多态性（SNP）RRM1 rs12806698 和 rs11031918 以及 DCTD rs7663494 与严重中性粒细胞减少症显著相关，hENT1 rs760370 和 hCNT3 rs7867504 以及 rs4877831 与严重白细胞减少症相关，CDA rs2072671、DCTD rs7663494 和 WEE1 rs3910384 与严重贫血相关，MTHFR rs1801133 与严格的 Bonferroni 校正后严重血小板减少症相关（P<.0038）。基因-基因相互作用分析确定了最佳的整体模型，包括严重白细胞减少症的 2 种相互作用模型（hCNT3 rs7867504 和 dCK rs12648166，P=0.0022）和严重贫血的 3 个基因模型（CDA rs207671、DCTD rs7663494 和 WEE1 rs3910384），其协同作用较强（P=0.0001）。单体型分析进一步强化了与血液学毒性的关联，其中 rs3910384 CC、rs2072671 AA、rs12648166 GG、rs7867504 CC 和 rs7663494 TT 的纯合基因型组合导致吉西他滨诱导的血小板减少症的遗传易感性增加。我们的结果表明，吉西他滨代谢途径基因与 WEE1 的基因-基因相互作用导致对吉西他滨引起的血液学毒性的易感性。此外，我们提出了一种有前途的数据挖掘分析方法（广义多因子降维）来检测和描述基因-基因相互作用。
