Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children

Abstract

Xenobiotic and folate metabolic pathways are important for the maintenance of genetic stability and may influence susceptibility to the development of childhood acute lymphoblastic leukaemia (ALL). In this study, we investigated 10 polymorphisms in 6 genes (GSTM1-present/null, GSTT1-present/null, GSTP1 1578A > G, NQO1 609C > T, MTHFR 677C > T, MTHFR 1298A > C, MTHFD1 1958G > A, 3'-TYMS 1494 6bp-deletion/insertion, 5'-TYMS 28bp-tandem repeats, and SLC19A1 80G > A) in a cohort of 185 Javanese children with ALL and 177 healthy controls. In ALL patients, none of the polymorphisms demonstrated a statistically significant association with ALL after correcting for multiple comparisons. Gender-stratified analysis showed that in girls, GSTT1-null genotype was associated with increased ALL risk (OR = 2.20; p = 0.027), while GSTP1 1578AG genotype was associated with reduced risk (OR = 0.43; p = 0.031). Strong linkage disequilibrium between the MTHFR 677C > T and 1298A > C polymorphisms was observed (D' = 1.0; r(2) = 0.072). The haplotypes 677C-1298C and 677T-1298A were associated with a reduced risk of ALL (OR = 0.68 and 0.64, respectively; gender-adjusted global p = 0.028). Classification and regression tree (CART) analysis was employed to identify potential high-order gene-gene interactions and cluster subjects into susceptibility groups. SLC19A1 80G > A emerged as the predominant polymorphism associated with risk of ALL. Individuals simultaneously carrying MTHFR 1298AA, 3'-TYMS 6bp deletion(s) and SLC19A1 80A-allele(s) were at higher disease risk (OR = 2.21; p < 0.001). On the contrary, simultaneous possession of MTHFR 1298CC, 3'-TYMS 6bp homozygosity and SLC19A1 80A-allele(s) conferred lower risk (OR = 0.25; p = 0.004). Carriage of NQO1 609C-allele amongst SLC19A1 80GG genotype was associated with lower risk (OR = 0.47; p = 0.003). In conclusion, our study has demonstrated the importance of gender and gene-gene interaction within the xenobiotic and folate pathways in modulating childhood ALL susceptibility.

The GSTP1 A1578G polymorphism and the risk of childhood acute lymphoblastic leukemia: results from an updated meta-analysis

“…As a result, GSTP1 is commonly studied for its effect on the susceptibility to acute myeloid leukemia (Allan et al, 2001). In recent years, a number of molecular epidemiologic studies have been conducted to evaluate the role of the A1578G polymorphism in the GSTP1 gene on childhood ALL risk; however, the results remain conflicting rather than conclusive (Krajinovic et al, 2002b;Balta et al, 2003;Barnette et al, 2004;Canalle et al, 2004;Clavel et al, 2005;Gatedee et al, 2007;Pigullo et al, 2007;Chan et al, 2011). Meta-analysis is a powerful statistical method that can provide a quantitative approach for pooling the results of different studies on the same topic, and thus a systematic review and meta-analysis of the association between the GSTP1 A1578G polymorphism and childhood ALL risk is of great value.…”

“…Their full texts were retrieved and carefully studied. Finally, a total of 8 eligible studies involving 1384 cases and 1755 controls were included in the pooled analyses (Krajinovic et al, 2002b;Balta et al, 2003;Barnette et al, 2004;Canalle et al, 2004;Clavel et al, 2005;Gatedee et al, 2007;Pigullo et al, 2007;Chan et al, 2011). The characteristics of the selected studies are summarized in Table 1.…”

Folate Pathway Gene Polymorphisms, Maternal Folic Acid Use, and Risk of Childhood Acute Lymphoblastic Leukemia

“…17,22,[24][25][26][27][28], methylenetetrahydrofolate dehydrogenase (MTHFD1; refs. 22,25,27,29), thymidylate synthetase (TS/ TYMS; refs. 17,20,22,25,[29][30][31][32], and reduced folate carrier (RFC1; refs.…”

“…22,25,27,29), thymidylate synthetase (TS/ TYMS; refs. 17,20,22,25,[29][30][31][32], and reduced folate carrier (RFC1; refs. 26,27,30,32).…”

Effects of the NQO1 609C>T Polymorphism on Leukemia Susceptibility: Evidence from a Meta-analysis

“…Previous researches have revealed the association between NQO1 609C>T polymorphism and leukemia susceptibility. However, the results were conflicting, including an increased risk (Wiemels et al, 1999;Smith et al, 2001;Lanciotti et al, 2005;Yamaguti et al, 2009;Yamaguti et al, 2010;Yamaguti et al, 2010), a reduced risk (Malik et al, 2006;Silveira Vda et al, 2010;Yeoh et al, 2010), and no association (Seedhouse et al, 2002;Kracht et al, 2004;Wu et al, 2004;Zhang, 2005;Clavel et al, 2005;Eguchi-Ishimae et al, 2005;Guillem et al, 2007;Voso et al, 2007;Gra et al, 2007;Bolufer et al, 2007;Begleiter et al, 2009;Chan et al, 2011;Lozic et al, 2011). The aim of this article is to review and evaluate the association between NQO1609C>T polymorphism and leukemia risk, mainly focusing on different ethnicity types.…”