High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia

Abstract

Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14-3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31-0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40-26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45-12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two-way interactions were mostly synergistic. These results suggest that high order gene-gene interactions play an important role in AL risk.

Glutathione S-transferase Gene Polymorphisms and Susceptibility to Acute Myeloid Leukemia: Meta-analyses

“…The basic data for every eligible study were extracted and are listed in Table 1. These studies were conducted in various populations of different ethnicities: 13 involved Caucasians (16,18,19,22,24 -26,29,31,33,34, 39,40), 8 involved East Asians (1,27,30,32,35 -38) and 8 involved mixed-race (2,5,11,17,20,21,23,28).…”

“…3C) and the recessive model (Fig. 3D) (2,20,27,34,37) (the study of Yuan et al was excluded in homozygotes contrast and recessive model as the number of GG genotype in the AML group was 0). No association between the SNP and the susceptibility to AML was found under any contrast model, and no heterogeneity was found under any model.…”

The Association between mrna Expression Levels of Ephx1 and Prognosis of Acute Myeloid Leukemia

“…Few studies on the association between EPHX1 gene expression and prognosis were reported in AML patients. Up to now only few reports shown EPHX1 gene polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia [12]. This study indicates an association between the increased mRNA expression levels of EPHX1 and poor treatment response and early drug resistance.…”

Association Between TP53 Gene Codon 72 Polymorphism and Acute Myeloid Leukemia Susceptibility: Evidence Based on a Meta-Analysis

“…Four studies were conducted in Asian populations [ 14 , 23 – 25 ] and 2 in white populations [ 22 , 26 ]. In terms of source of controls, 2 studies recruited controls from hospital (HB) [ 23 , 26 ] and 4 from general population (PB) [ 14 , 22 , 24 , 25 ]. The genotype distributions of controls from all included studies were consistent with HWE.…”