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Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia.

ABSTRACT: Folate is involved in the one-carbon metabolism that plays an essential role in the synthesis, repair, and methylation of DNA. We examined whether child's germline genetic variation in the folate pathway is associated with childhood acute lymphoblastic leukemia (ALL), and whether periconception maternal folate and alcohol intake modify the risk.Seventy-six single nucleotide polymorphisms (SNPs), including 66 haplotype-tagging SNPs in 10 genes (CBS, DHFR, FOLH1, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS), were genotyped in 377 ALL cases and 448 controls. Log-additive associations between genotypes and ALL risk were adjusted for age, sex, Hispanic ethnicity (when appropriate), and maternal race.Single and haplotype SNPs analyses showed statistically significant associations between SNPs located in (or adjacent to) CBS, MTRR, TYMS/ENOFS, and childhood ALL. Many regions of CBS were associated with childhood ALL in Hispanics and non-Hispanics (p < 0.01). Levels of maternal folate intake modified associations with SNPs in CBS, MTRR, and TYMS.Our data suggest the importance of genetic variability in the folate pathway and childhood ALL risk.

SUBMITTER: Metayer C

PROVIDER: S-EPMC3744066 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia.

Metayer Catherine C Scélo Ghislaine G Chokkalingam Anand P AP Barcellos Lisa F LF Aldrich Melinda C MC Chang Jeffrey S JS Guha Neela N Urayama Kevin Y KY Hansen Helen M HM Block Gladys G Kiley Vincent V Wiencke John K JK Wiemels Joseph L JL Buffler Patricia A PA

Cancer causes & control : CCC 20110712 9

<h4>Objective</h4>Folate is involved in the one-carbon metabolism that plays an essential role in the synthesis, repair, and methylation of DNA. We examined whether child's germline genetic variation in the folate pathway is associated with childhood acute lymphoblastic leukemia (ALL), and whether periconception maternal folate and alcohol intake modify the risk.<h4>Methods</h4>Seventy-six single nucleotide polymorphisms (SNPs), including 66 haplotype-tagging SNPs in 10 genes (CBS, DHFR, FOLH1, ...[more]

PMID: 21748308

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Project description: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.

Project description:BackgroundGenetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors.MethodsLong-term ALL survivors (n = 212; mean = 14.3 [SD = 4.77] years; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging. Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based functional neuroimaging. Statistical tests were 2-sided.ResultsSurvivors exhibited higher rates of impaired attention (20.8%), motor skills (42.2%), visuo-spatial memory (49.3%-58.3%), processing speed (20.1%), and executive function (24.3%-26.1%) relative to population norms (10%; P < .001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25, F(2,172) = 4.07, P = .019) and motor skills (monoamine oxidase A, F(2,125) = 5.25, P = .007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165) = 3.48, P = .033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135) = 3.8, P = .025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158) = 3.95, P = .021; MTHFD1rs1950902, F(2,154) = 5.55, P = .005) and glucocorticoid regulation (vitamin D receptor, F(2,158) = 3.29, P = .039; FKBP prolyl isomerase 5, F(2,154) = 5.6, P = .005). Additionally, MTHFD1rs2236225 and FKBP prolyl isomerase 5 were associated with altered brain function during attention and working memory (P < .05; family wise error corrected).ConclusionsResults extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.

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Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia.

Publications

Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia.

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