IDH2和TET2基因变异与欧洲、非洲人群急性髓系白血病患者阿糖胞苷敏感性的相关性

Association between genetic variants of isocitrate dehydrogenase 2 and ten-eleven-translocation protein 2 and cytarabine sensitivity in European and African populations with acute myeloid leukemia

目的探讨欧洲及非洲人群IDH2和TET2基因变异与阿糖胞苷药敏的相关性,促进个体化给药。方法培养来自人类基因组计划(HapMap)欧洲和非洲人群的细胞株,给予不同浓度的阿糖胞苷(1、5、40、80μmol·L^(-1))共培养72 h。应用Alamar Blue检测细胞存活曲线、阿糖胞苷的药物敏感性。梯形法计算阿糖胞苷生存曲线下面积(AUC)。Taqman PCR法检测两种人群IDH2和TET2基因多态性。结果欧洲人群样本中,与IDH2 rs2970356野生CC型和rs2970358野生AA型携带者的阿糖胞苷AUC相比,IDH2 rs2970356突变基因型CG/GG携带者、rs2970358突变基因型AG/GG携带者的阿糖胞苷AUC明显降低(rs2970356:CG/GG vs.CC,P<0.05;rs2970358:AG/GG vs.AA,P<0.05)。未检测到欧洲人群TET2的单核苷酸多态性与阿糖胞苷AUC有关。非洲人群样本中,IDH2 rs2970356突变基因型CG/GG携带者、TET2 rs2454206和rs11248047突变基因型AG/GG携带者的阿糖胞苷AUC明显降低(rs2970356:CG/GG vs.CC,P<0.05;rs2454206:AG/GG vs.AA,P<0.05;rs11248047:AG/GG vs.AA,P<0.05)。结论阿糖胞苷的敏感性受欧洲人群IDH2、非洲人群IDH2和TET2基因多态性影响。

AIM To explore the correlation between genetic variants of isocitrate dehydrogenase 2 （IDH2） and teneleven- translocation protein 2 （TET2） and cytarabine sensitivity in European （CEU） and African （YRI） populations in order to promote personalized medicine. METHODS Cell lines derived from persons of CEU ancestry or YRI ancestry from international HapMap project were cultured, and then exposed to cytarabine in different concentration （1, 5, 40, 80 μmol·L^-1） for 72 h. Percent cell survival values and cytarabine sensitivity depicted by the lower area under the survival curve （AUC） were determined by Alamar Blue assay. The AUC of cytarabine was calculated using the trapezoidal rule. Genotyping of IDH2 and TET2 was conducted by Taqman PCR assay. RESULTS Within CEU population samples, the AUC of cytarabine in IDH2 rs2970356 mutant CG/GG genotype carriers and rs2970358 mutant AG/GG genotype carriers were significantly lower than that in IDH2 rs2970356 CC genotype carriers and rs2970358 AA genotype carriers （rs2970356： CG/ GG vs. CC, P 〈 0.05 ; rs2970358： AG/GG vs. AA, P 〈 0.05）. There was no SNP in TET2 in CEU population associated with cytarabine sensitivity depicted by lower AUC. Within YRI population samples, the AUC of cytarabine in IDH2 rs2970356 mutant CC/CG genotype carriers, and in TET2 rs2454206 and rs11248047 mutant AG/GG genotype carriers were significantly lower than that in IDH2 rs2970356 GG genotype carriers, TET2 rs2454206 and rs11248047 AA genotype carriers （rs2970356： CG/GG vs. CC, P 〈 0.05; rs2454206： AG/GG vs.AA, P 〈 0.05; rs11248047： AG/GG vs.AA, P 〈 0.05）. CONCLUSION The cytarabine sensitivity might be influenced by gene polymorphism of IDH2 and TET2 in YRI populations, and only by gene polymorphism of IDH2 in CEU populations.