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

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: Our data suggest the importance of genetic variability in the folate pathway and childhood ALL risk.

Figures

Figure 1

a. “Sliding window” haplotype analyses for all subjects and by Hispanic ethnicity: Genes CBS, MTHFD1 and MTHFR Position of single nucleotide polymorphisms on chromosomes was based on dbSNP 37.1 database (http://www.ncbi.nlm.nih.gov/projects/SNP/). Results are presented for genes in which the p-value for at least one window was less than 0.10, and are shown separately for Hispanics and non-Hispanics when at least one single nucleotide polymorphisms within a given gene had a p-value for interaction by Hispanic ethnicity <0.10. Results are adjusted for child’s race, Hispanic ethnicity (when all children analyzed together), sex and age. b. “Sliding window” haplotype analyses for all subjects and by Hispanic ethnicity: Genes MTRR and TYMS Position of single nucleotide polymorphisms on chromosomes was based on dbSNP 37.1 database (http://www.ncbi.nlm.nih.gov/projects/SNP/). Results are presented for genes in which the p-value for at least one window was less than 0.10, and are shown separately for Hispanics and non-Hispanics when at least one single nucleotide polymorphisms within a given gene had a p-value for interaction by Hispanic ethnicity <0.10. Results are adjusted for child’s race, Hispanic ethnicity (when all children analyzed together), sex and age.

Figure 1

a. “Sliding window” haplotype analyses for all subjects and by Hispanic ethnicity: Genes CBS, MTHFD1 and MTHFR Position of single nucleotide polymorphisms on chromosomes was based on dbSNP 37.1 database (http://www.ncbi.nlm.nih.gov/projects/SNP/). Results are presented for genes in which the p-value for at least one window was less than 0.10, and are shown separately for Hispanics and non-Hispanics when at least one single nucleotide polymorphisms within a given gene had a p-value for interaction by Hispanic ethnicity <0.10. Results are adjusted for child’s race, Hispanic ethnicity (when all children analyzed together), sex and age. b. “Sliding window” haplotype analyses for all subjects and by Hispanic ethnicity: Genes MTRR and TYMS Position of single nucleotide polymorphisms on chromosomes was based on dbSNP 37.1 database (http://www.ncbi.nlm.nih.gov/projects/SNP/). Results are presented for genes in which the p-value for at least one window was less than 0.10, and are shown separately for Hispanics and non-Hispanics when at least one single nucleotide polymorphisms within a given gene had a p-value for interaction by Hispanic ethnicity <0.10. Results are adjusted for child’s race, Hispanic ethnicity (when all children analyzed together), sex and age.