1. Folate metabolism and risk of childhood acute lymphoblastic leukemia: a genetic pathway analysis from the Childhood Cancer and Leukemia International Consortium
- Author
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Metayer, Catherine, Spector, Logan G, Scheurer, Michael E, Jeon, Soyoung, Scott, Rodney J, Takagi, Masatoshi, Clavel, Jacqueline, Manabe, Atsushi, Ma, Xiaomei, Hailu, Elleni M, Lupo, Philip J, Urayama, Kevin Y, Bonaventure, Audrey, Kato, Motohiro, Meirhaeghe, Aline, Chiang, Charleston WK, Morimoto, Libby M, and Wiemels, Joseph L
- Subjects
Epidemiology ,Health Sciences ,Pediatric Cancer ,Cancer ,Clinical Research ,Rare Diseases ,Childhood Leukemia ,Human Genome ,Hematology ,Pediatric ,Genetics ,Minority Health ,Health Disparities ,2.1 Biological and endogenous factors ,Humans ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Folic Acid ,Polymorphism ,Single Nucleotide ,Child ,Case-Control Studies ,Female ,Male ,Genome-Wide Association Study ,Risk Factors ,Genetic Predisposition to Disease ,Child ,Preschool ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundPrenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.MethodsWe evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.ResultsNone of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.ConclusionsThis large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.ImpactGenetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.
- Published
- 2024