MDR1基因多态性与急性髓细胞白血病化学疗法结果的相关性研究

Correlation between MDR1 genetic polymorphism and prognosis in acute myeloid leukemia

目的研究多药耐药基因(MDR1)12外显子 C1236T、21外显子 G2677T/A、26外显子C3435T 基因多态性与急性髓细胞白血病(AML)化疗预后相关性。方法本研究纳入44位 AML 患者,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法以及直接测序的方法分析了患者MDR1第12、21、26位点基因型,并在诱导化疗第一疗程结束后进行骨髓形态学检查,结合临床指标判断患者是否完全缓解。x^2分析 MDR1各等位基因的分布是否符合 Hardy-Weinberg 平衡,完全缓解(CR)率与临床特征的相关性使用 x^2分析或 Fisher's精确检验。结果中国人 C1236T、G2677T/A 和C3435T 基因突变发生频率与其他种族相比差异有统计学意义,中国健康人以上三个位点基因型发生频率与急性髓细胞白血病患者相比差异无统计学意义。初发 AML 患者外周血白细胞数量与 CR 率有显著相关性(x^2=7.207,P=0.007);MDR1 C1236T 及 C3435T 基因多态性与 CR 率无显著相关性(P=0.349,P=0.074);MDR1 G2677T/A 多态性与 CR 率有显著相关性(x^2=6.214,P=0.045),携带G/G 基因型患者与非 G/G 基因型患者相比 CR 率较低(x^2=6.142,P=0.013);携带 MDR1 C3435TC/T 基因型患者与携带非 C/T 基因型患者相比 CR 率较低(x^2=3.991,P=0.046),同时显著低于 T/T基因型患者(x^2=5.134,P=0.023)。结论 MDR1外显子12、21、26基因型发生频率存在种族差异,AML 患者以上三个位点基因型发生频率与健康人相比差异无统计学意义。G2677T/A 基因多态性可以作为预测 AML 患者第一疗程是否 CR 的预测因素,为个体化给药提供理论基础。

Objective To assess the correlation of the multidrug resistance-1 （ MDR1 ） gene single nucleotide polymorphisms （SNP） C1236T, G2677T/A and C3435T with the outcome of induction chemotherapy in patients with de novo acute myeloid leukemia （AML）. Methods A total of 44 AML patients were enrolled in this study. Genotype of MDR1 C1236T, G2677T/A and C3435T were analyzed with PCR/PFLP assay. Bone marrow smear was made at the end of the first induction chemotherapy to estimate whether complete remission （CR） has been achieved with the clinical characteristics. The Hardy- Weinberg equilibrium for the MDR1 C1236T, G2677T/A and C3435T were tested using a Χ^2 analysis. Frequencies of genotype and allele in MDR1 C1236T, G2677T/A and C3435T were compared using a Χ^2 test or Fisher＇s test in terms of the clinical characteristics or achievement of CR. Results There were significant differences among ethnicities in exon 12, 21,26, but which were not between healthy chinese volunteers and AML patients. The CR rate of the group with the number of white blood cells （ WBC ） 〈 10 × 10^9/L were significantly higher than that of the group with WBC 〉 10 × 10^9/L （Χ^2 =7. 207,P=0. 007）. There was no correlation between the MDR1 C1236T and C3435T and CR rate （ P = 0. 349, P = 0. 074） , but MDR1 G2677T/A genetic polymorphisms were strong associated with the probability of CR（ Χ^2 = 6.214, P = 0. 045）. In addition, the CR was lower in G/G genotype at -2677 than non G/G genotype（Χ^2 =6. 142,P =0. 013 ）, and was lower in C/T genotype at -3435 than non C/T genotype （ Χ^2 = 3. 991, P = 0. 046 ）, even lower than T/T genotype （ Χ^2 = 5. 134, P = 0. 023 ）. Conclusion With important prognostic significance, MDR1 genetic polymorphisms, such as G2677T/A can predict whether complete remission can be achieved after the first course of induction chemotherapy.