The Interrelationship between Preconception Folate Nutritional Intake and Child Genetic Liability in the Risk of Childhood Acute Lymphoblastic Leukemia

Abstract Background: Prenatal maternal folate intake is associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL), but how this interacts with children’s genetic predisposition to folate deficiency remains unclear. Methods: We used Mendelian randomization to investigate the causal link among serum folate, total homocysteine, and B vitamins on ALL using independent genetic instruments. These were evaluated in two independent childhood ALL genome-wide association studies: the California Childhood Cancer Record Linkage Project and the California Childhood Leukemia Study, the latter with available self-reported periconceptional nutrition data. Logistic regressions assessed the interrelationship between maternal nutrition and children’s folate metabolism–related polygenic risk score (PRS) and methylenetetrahydrofolate reductase rs1801133 genotype. Results: Mendelian randomization analyses showed that higher genetically predicted serum folate was associated with reduced ALL risk [meta-analysis OR, 0.58; 95% confidence interval (CI), 0.34–0.97]. In Latinos, higher periconceptional folate intake from food mitigated and reversed the elevated risk associated with low folate PRS and the rs1801133 T allele. As the total folate intake increased, the odds of ALL shifted from 1.31 (95% CI, 1.01–1.69) to 0.53 (95% CI, 0.30–0.91) per 0.05-unit decrease in folate PRS and from 1.71 (95% CI, 1.02–2.88) to 0.24 (95% CI, 0.07–0.79) per T allele. In contrast, among non-Latino Whites, the corresponding ORs remained at 1.24 (95% CI, 1.07–1.43) and 1.40 (95% CI, 1.04–1.91). Conclusions: Maternal folate intake mitigated genetic liability against ALL in Latinos only, whereas genetic liability persisted in non-Latino Whites. Impact: This study highlights the need for personalized approaches to maximize the benefits of folic acid supplementation programs.