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Clinical impact of ABCC 1 and ABCC 2 genotypes and haplotypes in mediating imatinib resistance among chronic myeloid leukaemia patients
Author(s) -
Au A.,
Baba A. A.,
Azlan H.,
Norsa'adah B.,
Ankathil R.
Publication year - 2014
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12197
Subject(s) - haplotype , genotype , imatinib mesylate , abcc1 , multidrug resistance associated protein 2 , pharmacogenetics , myeloid leukemia , allele , imatinib , genetics , biology , medicine , oncology , gene , atp binding cassette transporter , transporter
Summary What is known and objective The introduction and success of imatinib mesylate ( IM ) has brought about a paradigm shift in chronic myeloid leukaemia ( CML ) treatment. However, despite the high efficacy of IM , clinical resistance develops due to a heterogeneous array of mechanisms. Pharmacogenetic variability as a result of genetic polymorphisms could be one of the most important factors influencing resistance to IM . The aim of this study was to investigate the association between genetic variations in drug efflux transporter ABCC 1 ( MRP 1 ) and ABCC 2 ( MRP 2 ) genes and response to IM in patients with CML . Methods We genotyped 215 M alaysian patients with CML (comprising of two groups with 108 IM resistant and 107 IM responsive) for polymorphisms of ABCC 1 (2012G>T and 2168G>A) and ABCC 2 (‐24C>T, 1249G>A and 3972C>T) genes. Genotype, allele and haplotype frequencies were compared between two groups of patients. Patients with CML were further stratified according to their clinical response to IM into those having cytogenetics and molecular responses, and the associations with genotypes were evaluated. Results and discussion We observed no significant differences in the distribution of any of the tested genotypes between the investigated groups. However, on evaluating the risk association, ABCC 2 T ‐24 G 1249 T 3972 haplotype was found to be associated with IM resistance ( P = 0·046). These results suggest that haplotype variants ‐24T and 3972T might be associated with lower expression of ABCC 2 protein and reduced transport activity and hence might be contributing to development of IM resistance. What is new and conclusion Our results suggest the ABCC 2 T ‐24 G 1249 T 3972 haplotype was associated with imatinib resistance. However, the evidence is as yet insufficient to establish this haplotype as a predictive biomarker for response to the drug.