title: Impact ofCYP3A4*18andCYP3A5*3Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia.
abstract: BACKGROUND
  Imatinib mesylate (IM), a selective inhibitor of the BCR-ABL tyrosine kinase, is a well-established first-line treatment for chronic myeloid leukemia (CML). IM is metabolized mainly by cytochrome P450 (CYP) in the liver, specifically the CYP3A4 and CYP3A5 enzymes. Polymorphisms in these genes can alter the enzyme activity of IM and may affect its response. In this study, the impact of two single-nucleotide polymorphisms (SNPs),CYP3A5*3(6986A>G) andCYP3A4*18(878T>C), on IM treatment response in CML patients (n= 270; 139 IM resistant and 131 IM good responders) was investigated.
  
  
  METHODS
  Genotyping ofCYP3A4*18andCYP3A5*3was performed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and treatment response was assessed by means of odds ratio (OR) with 95% confidence intervals calculated by logistic regression.
  
  
  RESULTS
  Our results indicated that CML patients carrying the heterozygous (AG) and homozygous variant (GG) genotype ofCYP3A5*3 were associated with a significantly lower risk of acquiring resistance with OR 0.171; 95% CI: 0.090-0.324,p< 0.001 and OR 0.257; 95% CI: 0.126-0.525,p< 0.001, respectively. Although CML patients carrying the heterozygous (TC) genotype ofCYP3A4*18showed a lower risk of acquiring resistance toward IM (OR 0.648; 95% CI: 0.277-1.515), the association was not statistically significant (p= 0.316). No homozygous variant (CC) genotype ofCYP3A4*18was detected among the CML patients.
  
  
  CONCLUSIONS
  It is concluded that polymorphism ofCYP3A5*3is associated with IM treatment response in Malaysian CML patients with carriers ofCYP3A5*1/*3andCYP3A5*3/*3genotypes posing lower risk for development of resistance to IM.
authors.affiliation: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan Malaysia.
authors.forename: Najlaa
authors.initials: N
authors.lastname: Maddin
authors.affiliation: Haemato-Oncology Unit and Department of Internal Medicine, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan Malaysia.
authors.forename: Azlan
authors.initials: A
authors.lastname: Husin
authors.affiliation: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan Malaysia.
authors.forename: Siew Hua
authors.initials: SH
authors.lastname: Gan
authors.affiliation: International Medical University Malaysia, Kuala Lumpur, 57000 Bukit Jalil, Wilayah Persekutuan Kuala Lumpur Malaysia.
authors.forename: Baba Abdul
authors.initials: BA
authors.lastname: Aziz
authors.affiliation: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan Malaysia.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Ankathil
keywords: CYP3A4*18; CYP3A5*3; Chronic myeloid leukemia; Imatinib mesylate; Single-nucleotide polymorphisms