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

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.