title: Do polymorphisms in MDR1 and CYP3A5 genes influence the risk of cytogenetic relapse in patients with chronic myeloid leukemia on imatinib therapy?
abstract: Influence of polymorphisms in the genes coding for imatinib transporters and metabolizing enzymes on cytogenetic relapse in patients with chronic myeloid leukemia (CML) is not known. One hundred and four patients (52 cases with cytogenetic relapse and 52 controls without relapse) with chronic-phase CML on imatinib therapy and have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms (SNPs) were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene, using PCR-RFLP method and validated by direct gene sequencing. Imatinib trough levels were measured using LC-MS/MS. Patients with CC genotype for MDR1-C1236T polymorphism were at significantly higher risk for cytogenetic relapse [OR =4.382, 95% CI (1.145, 16.774), p = .022], while those with TT genotype for MDR1-C3435T polymorphism had significantly lower risk of relapse [OR =0.309, 95% CI (0.134, 0.708), p = .005]. Imatinib trough levels were lower in patients with relapse compared to those without relapse (1551.4 ± 1324.1 vs. 2154.2 ± 1358.3 ng/mL; p = .041). MDR1-C3435T genotype [adjusted-OR: 0.266; 95% CI (0.111, 0.636); p = .003] and trough levels (p = .014) were independent predictors of relapse in multivariate analysis. To conclude, C1236T and C3435T polymorphisms in MDR1 gene and trough levels significantly influence the risk of cytogenetic relapse. MDR1-C3435T genotype might emerge as a potential biomarker to predict the risk of cytogenetic relapse in patients with CML.
authors.affiliation: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Harivenkatesh
authors.affiliation: b Medical Oncology , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.affiliation: b Medical Oncology , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Sameer
authors.initials: S
authors.lastname: Bakhshi
authors.affiliation: b Medical Oncology , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Atul
authors.initials: A
authors.lastname: Sharma
authors.affiliation: c Pediatrics (Genetics Unit) , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.affiliation: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Thirumurthy
authors.initials: T
authors.lastname: Velpandian
authors.affiliation: b Medical Oncology , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Gogia
authors.affiliation: c Pediatrics (Genetics Unit) , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Shivaram S
authors.initials: SS
authors.lastname: Shastri
authors.affiliation: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors.forename: Yogendra Kumar
authors.initials: YK
authors.lastname: Gupta
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003582:Cytogenetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012008:Recurrence; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A
keywords: Cytogenetic relapse; P-glycoprotein; imatinib mesylate; personalized medicine; pharmacogenetics; single nucleotide polymorphisms