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 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 (MR) to investigate the causal link between serum folate, total homocysteine (tHcy) and B vitamins on ALL using independent genetic instruments. These were evaluated in two independent childhood ALL GWASs, the California Childhood Cancer Record Linkage Project and 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 MTHFR rs1801133 genotype.

Results: MR analyses showed that higher genetically predicted serum folate was associated with reduced ALL risk (meta-analysis OR = 0.58; 95% 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 (NLWs), 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, while genetic liability persisted in NLWs.

Impact: This study highlights the need for personalized approaches to maximize the benefits of folic acid supplementation programs.