Polymorphisms of CYP1B1, CYP3A4, CYP3A5, GSTM1, GSTTT1 and SULT1A1 Associated with Early Age Acute Leukemia

Abstract

The acute leukemia causation pathway has been postulated to be a multistep process with interaction between environmental and genetic susceptibility factors. Based on previous observation, early age leukemia (EAL) was associated with maternal hormone exposures.The aim of the study was to explore whether polymorphisms in genes of the estrogen-metabolism pathway could be related to EAL. The study included 754 children, being 350 EAL and 404 age-matched controls and 134 mothers of EAL and controls. Polymorphisms of CYP1B1 (rs1056836), CYP3A4 (rs2740574), and CYP3A5 (rs776746) were identified by RFLP; GSTM1 and GSTT1 deletions were detected by multiplex PCR, whilst an internal control (CYP1A1) was co-amplified; SULT1A1 rs9282861 and rs1801030 were genotyped on PyroMark Q24. Gene expression was performed by Real-time PCR using Platinum® SYBR® Green qPCR SuperMix. Logistic regression was used to evaluate the associations adjusted on skin color. The risk was determined by calculating odds ratios (ORs) with 95% confidence interval (CI). CYP1B1 and CYP3A5 expression analyzed using Kruskal-Wallis and Dunn's Multiple Comparison tests. GSTT1*0, CYP3A4*1B, and CYP3A5*1 were associated with an increased risk of acute myeloid leukemia (AML) after adjusting for multiple comparisons regarding non-whites and male children (OR 1.91, 95% CI: 1.12, 3.28; OR 2.44, 95% CI: 1.10, 5.43; OR 1.98, 95% CI: 0.96, 4.10, respectively). CYP1B1 was not expressed in 57.1% of EAL cases; expression varied by genotype, gender, and leukemia subtype. AML was associated with distinct modulations: CYP1B1*3/SULT1A1*3 decreased and CYP3A4*1B/SULT1A1*2 increased EAL risk (OR 0.24, 95% CI: 0.10, 0.55; OR 2.06, 95% CI: 0.96, 4.42, respectively). Maternal-fetal genotypes were associated with EAL based on CYP3A4*1B and GSTT1*0. Therefore, genetic polymorphisms involved in estrogen metabolism confer different susceptibilities for EAL, modulating leukemia subtype in males.