ABCB1 (MDR1, P-Glycoprotein) C3435T Gene Polymorphism and its Possible Association with Chronic Myeloid Leukemia Prognosis

Order of Publishing in Issue: 
5
Volume :2
Issue :4
October, 2008
Page No: 
514 -522
Authors: 
K.Sailaja, D.Surekha, D.Nageswara Rao, D.Raghunadha Rao1, S.Vishnupriya*
Address: 
Department of Genetics, Osmania University, Hyderabad, India
Address: 
1Nizam’s Institute of Medical Sciences, Hyderabad, India

Adenosine triphosphate-binding cassette B1 (MDR1- multiple drug resistance gene1), a drugtransporter gene encodes a transmembrane - glycoprotein (P-gp), which functions as an effluxpump for various structurally unrelated anticancer agents and toxins. Our main objective is to studyMDR1 gene polymorphism at C3435T in chronic myeloid leukemia (CML) to understand itsassociation with development and response to drug (Imatinib) treatment. The present study comprises of 150 CML cases and 150 age and sex matched controls. MDR1 C3435Tpolymorphism was analyzed through polymerase chain reaction followed by restriction enzymedigestion (PCR-RFLP). The MDR1 genotype distribution revealed elevated frequency of TTgenotype in CML patients (34%) when compared to controls (28.67%). Within the disease group,T allele frequency (0.59) was elevated as compared to C allele frequency (0.41). Thefunctional significance of MDR1 C3435T polymorphism with respect to Imatinib (P-gpsubstrate) treatment was also studied in terms of hematological and cytogenetic responses.Patients without hematological response had higher frequency of TT genotype (52.63%) ascompared to those with major (32.23%) or minor (20%) hematological response. Whereas patientswithout cytogenetic response had higher frequency of CC genotype (27.03%) comparedto those with major (15.15%) or minor (10.64%) cytogenetic response When the data wascompared in relation to combination of both typesof responses, the frequency of CC genotype was increased significantly in cytogenetic nonrespondersand the increase was found to be inversely proportional to the degree of cytogenetic response. This could be attributed toover expression of P-gp in individuals with CC genotype that might have resulted in increasedefflux of Imatinib, a P-gp substrate leading to drug resistance. The present study indicates the possible association of MDR1 (C3435T) polymorphismwith increased risk for development of CML in T allele carriers

Keywords: 
MDR1 gene, Chronic myeloid leukemia, Single nucleotide polymorphism, PCR-RFLP.
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