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

Area of Science:

• Nutritional Epidemiology
• Genetic Epidemiology
• Pediatric Oncology

Background:

• Prenatal folate intake is linked to lower childhood acute lymphoblastic leukemia (ALL) risk.
• The interaction between maternal folate and a child's genetic susceptibility to folate deficiency in ALL etiology is not well understood.

Purpose of the Study:

• To investigate the causal relationship between folate, B vitamins, homocysteine, and childhood ALL risk.
• To examine how maternal nutrition interacts with genetic factors influencing folate metabolism in children with ALL.

Main Methods:

• Mendelian randomization analysis using genetic instruments for serum folate, homocysteine, and B vitamins.
• Evaluation in two large childhood ALL genome-wide association studies.
• Logistic regression to assess interactions between maternal nutrition, polygenic risk scores (PRS), and MTHFR genotype.

Main Results:

• Higher genetically predicted serum folate was associated with a reduced risk of childhood ALL (OR, 0.58; 95% CI, 0.34-0.97).
• In Latino populations, increased periconceptional folate intake reversed the elevated ALL risk associated with low folate PRS and the MTHFR rs1801133 T allele.
• In contrast, genetic risk for ALL persisted in non-Latino Whites despite folate intake.

Conclusions:

• Maternal folate intake can mitigate genetic susceptibility to ALL, but this effect appears ethnicity-specific, observed only in Latinos.
• Genetic predisposition to folate deficiency remains a risk factor for ALL in non-Latino Whites, irrespective of folate intake.
• Personalized folic acid supplementation strategies are crucial for maximizing benefits and mitigating ALL risk across diverse populations.