METHODS: Single nucleotide polymorphisms were genotyped using pyrophosphate sequencing. Plasma trough levels of imatinib were measured using liquid chromatography-tandem mass spectrometry.
RESULTS: Patients carrying the TT genotype for ABCB1 (rs1045642, rs2032582, and rs1128503), GG genotype for CYP3A5-rs776746 and AA genotype for ABCG2-rs2231142 polymorphisms showed higher concentration of imatinib. Patients with T allele for ABCB1 (rs1045642, rs2032582, and rs1128503), A allele for ABCG2-rs2231142, and G allele for CYP3A5-rs776746 polymorphisms showed better cytogenetic response and molecular response. In multivariate analysis, carriers of the CYP3A5-rs776746 G allele exhibited higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR). Similarly, patients with the T allele of ABCB1-rs1045642 and rs1128503 demonstrated significantly increased CCyR rates. Patients with the A allele of ABCG2-rs2231142 were associated with higher MMR rates. The AA genotype for CYP3A5-rs776746, and the CC genotype for ABCB1-rs104562, and rs1128503 polymorphisms were associated with a higher risk of imatinib failure. Patients with the G allele for CYP3A5-rs776746 exhibited a higher incidence of anemia, and T allele for ABCB1-rs2032582 demonstrated an increased incidence of diarrhea.
CONCLUSIONS: Genotyping of ABCB1, ABCG2, and CYP3A5 genes may be considered in the management of patients with CML to tailor therapy and optimize clinical outcomes.
方法:使用焦磷酸测序对单核苷酸多态性进行基因分型。使用液相色谱-串联质谱法测量伊马替尼的血浆谷水平。
结果:携带ABCB1TT基因型的患者(rs1045642、rs2032582和rs1128503),CYP3A5-rs776746的GG基因型和ABCG2-rs2231142多态性的AA基因型显示伊马替尼浓度较高。ABCB1的T等位基因患者(rs1045642,rs2032582和rs1128503),ABCG2-rs2231142的等位基因和CYP3A5-rs776746多态性的G等位基因显示出更好的细胞遗传学反应和分子反应。在多变量分析中,CYP3A5-rs776746G等位基因的携带者表现出更高的完全细胞遗传学反应(CCyR)和主要分子反应(MMR)。同样,ABCB1-rs1045642和rs1128503的T等位基因患者的CCyR率显著升高.ABCG2-rs2231142等位基因A的患者与较高的MMR率相关。CYP3A5-rs776746的AA基因型和ABCB1-rs104562的CC基因型以及rs1128503多态性与伊马替尼失败的较高风险相关。CYP3A5-rs776746的G等位基因患者表现出更高的贫血发生率,ABCB1-rs2032582的T等位基因显示腹泻发生率增加。
结论:ABCB1,ABCG2和CYP3A5基因的基因分型可以在CML患者的治疗中考虑,以调整治疗和优化临床结果。