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. 2016;4(2):303-314.
doi: 10.1007/s40487-016-0035-x. Epub 2016 Nov 21.

Impact of CYP3A4*18 and CYP3A5*3 Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia

Najlaa Maddin  1 , Azlan Husin  2 , Siew Hua Gan  1 , Baba Abdul Aziz  3 , Ravindran Ankathil  1
Affiliations

Impact of CYP3A4*18 and CYP3A5*3 Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia

Najlaa Maddin et al. Oncol Ther. 2016.

Abstract

Introduction: 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) and CYP3A4*18 (878T>C), on IM treatment response in CML patients (n = 270; 139 IM resistant and 131 IM good responders) was investigated.

Methods: Genotyping of CYP3A4*18 and CYP3A5*3 was 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 of CYP3A5*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 of CYP3A4*18 showed 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 of CYP3A4*18 was detected among the CML patients.

Conclusion: It is concluded that polymorphism of CYP3A5*3 is associated with IM treatment response in Malaysian CML patients with carriers of CYP3A5*1/*3 and CYP3A5*3/*3 genotypes posing lower risk for development of resistance to IM.

Keywords: CYP3A4*18; CYP3A5*3; Chronic myeloid leukemia; Imatinib mesylate; Single-nucleotide polymorphisms.

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Figures

Fig. 1
Fig. 1
Gel electrophoresis after RFLP analysis for a CYP3A4*18 (following digestion with Msp1) and b CYP3A5*3 (following digestion with Ssp1). a Lane 1 contained a 100-bp ladder. Lanes 2 and 4 indicated a homozygous wild-type individual. Lane 3 showed a heterozygous individual. b Lane 1 contained a 100-bp ladder. Lanes 2, 3 and 6 showed homozygous variants (GG). Lane 4 indicated a homozygous wild type (AA). Lanes 5 and 7 showed a heterozygous individual. Lane 8 contained a 50-bp ladder
Fig. 2
Fig. 2
Direct DNA sequencing results showing part of the electropherogram for a CYP3A4*18 and b CYP3A5 *3. a Top panel: i a homozygous wild-type individual; ii a heterozygous individual. b Bottom panel: i homozygous wild-type, ii heterozygous and iii homozygous variants
Fig. 3
Fig. 3
LD blocks of rs28371759 (CYP3A4*18) and rs776746 (CYP3A5*3). The plot shows the r 2 value as pair-wise measure of LD
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