Abstract
In this study we investigated whether polymorphisms in the folate pathway influenced the risk of childhood acute lymphoblastic leukemia (ALL) or the survival rate of the patients. For this we selected and genotyped 67 SNPs in 15 genes in the folate pathway in 543 children with ALL and 529 controls. The results were evaluated by gender adjusted logistic regression and by the Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) methods. Bayesian structure based odds ratios for the relevant variables and interactions were also calculated. Altogether 9 SNPs in 8 genes were associated with altered susceptibility to ALL. After correction for multiple testing, two associations remained significant. The genotype distribution of the MTHFD1 rs1076991 differed significantly between the ALL and control population. Analyzing the subtypes of the disease the GG genotype increased only the risk of B-cell ALL (p = 3.52×10−4; OR = 2.00). The GG genotype of the rs3776455 SNP in the MTRR gene was associated with a significantly reduced risk to ALL (p = 1.21×10−3; OR = 0.55), which resulted mainly from the reduced risk to B-cell and hyperdiploid-ALL. The TC genotype of the rs9909104 SNP in the SHMT1 gene was associated with a lower survival rate comparing it to the TT genotype (80.2% vs. 88.8%; p = 0.01). The BN-BMLA confirmed the main findings of the frequentist-based analysis and showed structural interactional maps and the probabilities of the different structural association types of the relevant SNPs especially in the hyperdiploid-ALL, involving additional SNPs in genes like TYMS, DHFR and GGH. We also investigated the statistical interactions and redundancies using structural model properties. These results gave further evidence that polymorphisms in the folate pathway could influence the ALL risk and the effectiveness of the therapy. It was also shown that in gene association studies the BN-BMLA could be a useful supplementary to the traditional frequentist-based statistical method.
Highlights
Acute lymphoblastic leukemia (ALL) is the most frequent haematopoetic malignancy in childhood worldwide [1], and in Hungary with about 60–80 new cases registered a year (Hungarian Children Cancer Registry)
By analyzing the data with BN-BMLA we intend to refine the dependency relationships of factors, e.g. we investigate whether a variable is directly relevant or its association is only mediated.BN-BMLA was recently extended with Bayesian effect size estimation providing a hybrid measure, the Bayesian structure based odds ratio, which characterizes the parametric and strong relevance aspects of factors [19]
The frequentist statistical analysis revealed that 9 SNPs in 8 genes (ABCB1, DHFR, FPGS, MTHFD1, MTR, SHMT1, TYMS, MTRR) reached the p,0.05 values (Table S4), but due to the multiple testing, statistical corrections were applied
Summary
Acute lymphoblastic leukemia (ALL) is the most frequent haematopoetic malignancy in childhood worldwide [1], and in Hungary with about 60–80 new cases registered a year (Hungarian Children Cancer Registry). In the last years several genome wide and candidate gene association studies have tried to explore the genetic background of the disease, and revealed a number of genes and genetic variations, which might influence the risk of the disease or the response to the therapy [2,3]. Genetic variations of genes encoding pivotal regulator and transport enzymes of the folate cycle (e.g. MTHFD1, MTRR, MTR, MTHFR, DHFR, GGH, SLCO1B1) could influence the available folate in the cells, and might alter the susceptibility to ALL and the response to the therapy [7,8,9,10,11,12]. We selected 67 SNPs in 15 genes (DHFR, MTHFD1, MTHFR, MTRR, MTR, SHMT1, TYMS, ABCB1, FPGS, GGH, GSTP1, SLCO1B1, SLC19A1, SLC22A8, TPMT) in the folate metabolic pathway (Figure 1 and Table S1)
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