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The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukemia

From the Laboratory of Molecular Biology, Department of Medical Biopathology, Hospital Universitario La Fe, Valencia, Spain (PB, MC, EB); Cytogenetics, Service of Hematology, Hospital Universitario La Fe, Valencia, Spain (JC); Department of Genetics, University of Navarra, Pamplona, Spain (M-JC); Hematology, Hospital Clínic de Barcelona, Barcelona, Spain (DC); Service of Hematology, Hospital Reina Sofia, Córdoba, Spain (JR-G); Clinical Hematology, Service of Hematology, Hospital Universitario La Fe, Valencia, Spain (MAS)

Correspondence: Pascual Bolufer Gilabert, Laboratorio de Biología Molecular, Escuela de Enfermería 7ª. Hospital Universitario la Fe, Avda. Campanar 21, 46009 Valencia, Spain. E-mail: bolufer_pas{at}gva.es

Background and Objectives: We examined common polymorphisms in the genes for glutathione S-transferase (GST), cytochrome P450 (CYP), quinone oxoreductase (NQO1), methylene tetrahydrofolate reductase (MTHFR), and thymidylate synthetase (TYMS) and the role of gender associated with the susceptibility to de novo acute leukemia (AL).

Design and Methods: We conducted a case-control study analyzing the prevalence of the polymorphisms CYP1A1*2A, CYP2E1*5B, CYP3A4*1B, del{GSTT1}, del{GSTM1}, NQO1*2, MTHFR C6777, and TYMS 2R/3R in 443 patients with AL [302 with acute myeloblastic leukemia (AML) and 141 with acute lymphoblastic leukemia (ALL)] and 454 control volunteers, using polymerase chain reaction (PCR)-based methods.

Results: We found a higher incidence of del{GSTT1} in patients with AML than among controls (25.6% vs. 13.7%, OR=2.2, p<0.001) and a higher incidence of NQO1*2 homozygosity (NQO1*2_hom.) in males with the M3 FAB subtype than in control males (8.6% vs. 2.2%, OR=4.9, p=0.02). The del{GSTT1} and NQO1*2_hom. polymorphisms increased the risk of ALL (OR=2.2 and 3.0, p=0.001 and 0.003, respectively). The higher risk conferred by NQO1*2_hom. and del{GSTT1} mainly affected males (OR=6.1 and 2.4; p=0.002 and 0.005, respectively).

Interpretation and Conclusions: Males harboring NQO1*2_hom. and del{GSTT1} polymorphisms showed a higher risk than females of developing AL. Thus, gender might influence the risk of AL associated with these genetic polymorphisms.

Key words: polymorphisms, gender, risk, drug-metabolizing enzymes, acute leukemia.

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