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Genetic variations in influx transporter gene SLC22A1 are associated with clinical responses to imatinib mesylate among Malaysian chronic myeloid leukaemia patients

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Abstract

Imatinib mesylate (IM), a well-established gold standard drug in the treatment of chronic myeloid leukaemia (CML), is a synthetic tyrosine kinase inhibitor. Despite excellent efficacy, a significant number of patients on IM therapy develop resistance to IM. Currently, great focus has been laid on the effect of interindividual pharmacogenetic variability on IM treatment responses. IM uptake is mediated by the hOCT1 protein encoded by the solute carrier 22 gene (SLC22A1). The current study investigated the impact of few single-nucleotide polymorphisms (SNPs) of SLC22A1 on mediating resistance and/or good response to IM among 278 Malaysian CML patients (146 IM-resistant group and 132 IM good response group) undergoing IM therapy on 400 mg daily. Our results showed that the allelic frequencies of heterozygous (CG) and homozygous variant (GG) genotypes of SLC22A1 C480G were significantly higher in the IM-resistant group compared with the IM good response group (41.8% versus 30.3% and 10.9% versus 4.5% with P values of 0.047 and 0.048, respectively). On evaluating the association of genotypes with risk of IM resistance development, heterozygous (CG) and homozygous (GG) variant genotypes showed significantly higher risk for developing resistance to IM treatment with odds ratio (OR): 1.901 (95% confidence interval (CI): 1.142–3.163, \(P=0.013\)) and 3.324 (95% CI: 1.235–8.947, \(P=0.017\)), respectively. Two SNPs and two insertions/deletions were detected in exon 7 of SLC22A1. For exon 7, 1222AA carriers together with the presence of both the 8-bp insertion and 3-bp deletion, and M420del alleles showed higher possibility of developing resistance towards IM treatment. Our results warrant the need of genotyping this SNP in terms of modulating IM treatment in CML patients.

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Acknowledgements

This study was supported by USM APEX grant no. 1002/PPSP/910340. The cooperation of Dr Ai Sim Goh (Hospital Pulau Pinang), Dr Padmini Menon (Hospital Ipoh), Dr Chew Teng Keat (Hospital Kuching) Prof. Rosline Hassan (Universiti Sains Malaysia), Prof. S. A. W. Fadilah (UKM Medical Center) and Dr Alan Teh (Sime Darby Medical Center) in patient recruitment is gratefully acknowledged.

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Authors and Affiliations

  1. Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 , Kubang Kerian, Kelantan, Malaysia

    Siti Maziras Makhtar & Ravindran Ankathil

  2. Haemato-Oncology Unit and Department of Internal Medicine, School of Medical Sciences, Universiti Sains Malaysia, 16150 , Kubang Kerian, Kelantan, Malaysia

    Azlan Husin

  3. International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000 , Bukit Jalil, Kuala Lumpur, Malaysia

    Abdul Aziz Baba

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  1. Siti Maziras Makhtar
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  2. Azlan Husin
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  4. Ravindran Ankathil
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Correspondence to Ravindran Ankathil.

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Corresponding editor: Dhavendra Kumar

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Makhtar, S.M., Husin, A., Baba, A.A. et al. Genetic variations in influx transporter gene SLC22A1 are associated with clinical responses to imatinib mesylate among Malaysian chronic myeloid leukaemia patients. J Genet 97, 835–842 (2018). https://doi.org/10.1007/s12041-018-0978-9

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  • DOI: https://doi.org/10.1007/s12041-018-0978-9

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