The Singnificance Of The Expression Of The CYP3A5 And MDR1 Genetic Polymorphism In Childhood Acut Lymphoblastic Leukemia

Objective: To study the frequency distribution patterns of genotype polymorphism of Cytochrome p450â…¢A 5(CYP3A5) CYP3A5 -6986A/G,multidrug resistance gene1(MDR1) C3435T,C1236T,and G2677T/A in children with acute lymphoblastic leukemia(ALL) and healthy control, we approach whether the CYP3A5 -6986A/G,MDR1 C3435T,C1236T and G2677T/A polymorphism is related to vulnerability to children acute lymphoblastic leukemia.Methods: 1,A case-control study was carried out to compare the distribution of genotype and genetic frequency of CYP3A5 -6986A/G,MDR1 C3435T,C1236T and G2677T/A between ALL(n=176) and control individuals(n=170) with Single Nucleotide Polymorphisms-shot( SNP-shot) method(some data of the CYP3A5 -6986A/G are from our study in 2007).2,Using flow cytometry(FCM) to examine P-glycoprotein(P-gp) activity at preliminary diagnosis,after prednisone induction essay and after VDLD course of treatment,its association with the genetic polymorphism of MDR1 C3435T,C1236T and G2677T/A were analyzed.3,we also analyse the sex,age,immuno-phenotype,chromosome karyotype and fusion gene whether they are associated with genetic polymorphism of CYP3A5 -6986A/G,MDR1 C3435T,C1236T,G2677T/A and P-gp activity.Result: 1. Three genotypes (G/A, G/G and A/A) of CYP3A5 -6986A/Gpolymorphism, three genotypes (C/C, C/T and T/T) of MDR1 C3435T polymorphism, three genotypes (C/C, C/T and T/T) of MDR1 C1236T polymorphism and six genotypes (A/A, G/A, G/G, G/T, T/T and T/A) of MDR1 G2677T/A polymorphism were found.2. There was significant difference in the distribution of genotype A/A of CYP3A5 -6986A/G between the group of ALL and controls patients(22/267 vs 43/290, p=0.030); There was significant difference in the distribution of genotype T/T of MDR1 C3435T between the group of ALL and controls patients(85/176 versus 20/170, p<0.0001). 3. The haplotype TTT/TTT of MDR1 C3435T, C1236T, G2677T/A distribute different between standard risk,median risk,high risk(6/88 vs 1/46 vs 7/42,p=0.037).4. The haplotype CTG/CCA of MDR1 C3435T,C1236T,G2677T/A distribute more in the older than ten-year-old cases than younger than ten-year(5/20 vs 7/146,p=0.006);The genotype CT of MDR1 C1236T distribute more in the older than six-year-old cases than younger than six-year(36/26 vs 46/65,p=0.036).5. The patients with T/T of MDR1 C3435T had highter risk of fatal outcome when compared the C+ carriers(p=0.03); The patients with C/T of MDR1 C1236T had highter risk of fatal outcome when compared the C/Cand T/T carriers(p=0.047).6. The SNPs of MDR1 do not effect the P-gp activity.Conclusion:1. There was significant difference in the distribution of genotype of CYP3A5 -6986A/G between the group of ALL and controls patients;The patients with T/T of MDR1 C3435T are might be contributed to the susceptibility of acute lymphoblastic leukemia.2. The haplotype of MDR1 could be the clinical parameter at diagnosis.3. The SNPs of MDR1 may effect the EFS of ALL.4. The SNPs of MDR1 whether affect of the P-gp activity need to study sequencely .