Background: Despite
acceptable results of imatinib in the treatment of chronic myeloid
leukemia (CML), some patients fail to acquire a complete cytogenetic
response (CCyR), which may be caused by polymorphisms in the
pharmacogenetic genes. The study aimed to evaluate the association of
two polymorphisms in the ABCB1 and ABCG2 genes with cytogenetic response
to imatinib and the risk of CML development.
Methods: We
genotyped ABCB1 (c .2677G/T/A) and ABCG2 (c .421C/A) polymorphisms by
PCR-RFLP, T-ARMS-PCR methods in 111 patients with CML and 102 sex- and
age-matched healthy subjects. CCyR was determined by standard chromosome
banding analysis (CBA).
Results: Analysis
of polymorphisms showed significant association of ABCG2 c.421CA
genotype (p < 0.0001; OR = 0. 17), and ABCG2c.421A allele (p <
0.0001; OR = 0.31) with decreased risk of CML. Moreover, ABCB1c.2677GT-
ABCG2c.421CC combined genotype (p = 0.017; OR = 4.20) was associated
with increased risk of CML. Analysis of the joint effect of SNP-smoking
combination showed that smoker subjects with the ABCB1c.2677GG/GT (p =
0.001; OR = 15.96, p = 0.001; OR = 8.13, respectively) or ABCG2c.421CC
genotypes (p = 0.001; OR = 5.82) had the increased risk of CML, while
the risk of the CML in non-smokers carrying the ABCG2c.421CA (p <
0.0001; OR = 0. 18) genotype was strongly decreased compared with
reference group. Regarding drug response, ABCG2c.421 CC/CA genotypes in
the smoker patients were associated with an increased risk of resistance
to imatinib (p < 0.0001; OR = 7.02, p = 0.018; OR = 4.67,
respectively).
Conclusion: Our
results suggest the impact of ABCG2c .421C/A polymorphism on CML
development, and smoking may have a synergistic role in the risk of CML
and resistance to imatinib.