Effect of hOCT1 Polymorphism on Imatinib Mesylate Action in CML Patients

Objective: To evaluate effect of human organic cation transporter 1((hOCT1) polymorphism on Imatinib Mesylate (IM) in Chinese CML patients.

Material and Methods: Totally 76 patients were enrolled(53 CML, 23 non-CML patients). The 53 CML patients were categorized as optimal-, suboptimal-and failure ones, according to their clinical response. 2 Tibetan nationality Chinese patients were described separately. In this study, amplification refractory mutation system (ARMS)-polymerase chain reaction was used to amplify the polymorphism gene segment of hOCT1- P283L, R287G, M408V.

Results:

1. In the 74 Chinese Han subjects: ‡@ The frequencies of CC ACT ATT genotype in hOCT1- P283L were 35.14%,50.00%,14.86%; the allele C AT frequencies were 60.14% and 39.86%, respectively; ‡A The frequencies of CC ACG AGG genotype in hOCT1- R287G were 51.35%,39.19%,9.46% Gthe allele C AG frequencies were 70.95% and 29.05%, respectively G‡B The frequencies of AA AAG AGG genotype in hOCT1- M408V were 28.37%,52.70%,18.92% Gthe allele A AG frequencies were 54.73% and 45.27%, respectively.

2. The genotypes of hOCT1- P283L, R287G, M408V in 2 Tibetan nationality Chinese were CC ACC AAG and CC ACG AAG, respectively.

3. In the CML patients with suboptimal response (group IIa), the frequency of hOCT1-283T allele was predominant, which was 55.56%, compared with that of 30.77% in the optimal response group(group I). The difference in the frequency distribution of hOCT1-P283L allele between two groups was statistically significance(X²=5.406,P=0.020).

4. The frequencies of CC ACG AGG genotype of hOCT1-R287G in patients with suboptimal response group(group IIa) were 38.89%,61.11%,0 Gcompared with that of 57.69%,30.77%,11.54% in patients with optimal group (group I). A significant difference was found in the frequency distribution of hOCT1-R287G genotype between two groups(X²=6.149,P=0.046). In group IIa, the CG genotype was more common than group I, but no GG genotype.

5. Non-significant difference was found in the frequency distribution of hOCT1-P283L, R287G, M408V genotype and allele between patients with failure response group (group IIb) and group IIa.

6. Non-significant difference was found in the frequency distribution of hOCT1- M408V genotype and allele among the 3 groups: I AIIa and IIb (X² =0.268,P=0.874 GX²a =0.988,Pa=0.610 GX²b =2.819, Pb=0.244).

Conclusion

1. Three coding single nucleotide polymorphisms (cSNP) --- hOCT1- P283L, R287G, M408V, were found in the human Organic Cation Transporter 1 gene from 74 Chinese Han individuals. The frequency distributions of their genotype and allele were different from that reported by others.

2. The polymorphisms of hOCT1-R287G, M408V were found in 2 Tibetan nationality Chinese subjects.

3. In this current study, hOCT1 gene polymorphism was associated with the long-term molecular response of CML patients administered with IM, the CG genotype of hOCT1-R287G and T allele of hOCT1- P283L in the suboptimal response group are prevalent; there is no specific association between hOCT1-M408V and patients’ response. This indicated that the polymorphism of hOCT1- P283L, R287G might be a valuable factor in predicting patients’ response.

4. In our study, there was no specific correlation between the polymorphism of hOCT1- P283L, R287G, M408V and CML patients resistant to IM secondarily.