Roles of genetic polymorphisms in the folate pathway in childhood acute lymphoblastic leukemia evaluated by Bayesian relevance and effect size analysis

PLoS One. 2013 Aug 5;8(8):e69843. doi: 10.1371/journal.pone.0069843. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Bayes Theorem*
  • Child
  • Child, Preschool
  • Female
  • Folic Acid / metabolism*
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Infant
  • Male
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics
  • Middle Aged
  • Minor Histocompatibility Antigens
  • Polymorphism, Genetic / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Survival Rate
  • Young Adult

Substances

  • Minor Histocompatibility Antigens
  • Folic Acid
  • MTHFD1 protein, human
  • Methylenetetrahydrofolate Dehydrogenase (NADP)

Grants and funding

This study was supported by OTKA (Hungarian Scientific Research Fund): K81941 (C. Szalai); TS/2 044707 (A. Falus); and the Economic Competitiveness Operational Program, Hungary GVOP 3.1.1-2004-05-0022/3.0 (A Falus, DJ Erdélyi); OTKAPD (Hungarian Scientific Research Fund):76348 (P.Antal), Bolyai Grant (Hungarian Academy of Science): (P.Antal) and NKTH (National Research and Technology) TECH_08-A1/2-2008-0120: (A. Falus, C. Szalai, P. Antal). This work is connected to the scientific program of the “Development of quality-oriented and harmonized R+D+I strategy and functional model at BME” project. This project is supported by the New Széchenyi Plan (Project ID: TÁMOP-4.2.1/B-09/1/KMR-2010-0002). Web pages for the funding organizations: OTKA: http://www.otka.hu/NKTH: www.nih.gov.hu ETT: http://www.ett.hu/palyazat.htm Bolyai Grant: http://www.bolyaitestamentum.hu/?m=24 The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.