Abstract 2281: The interrelationship between maternal periconception folate nutritional intake and child’s genetic liability in the etiology of childhood acute lymphoblastic leukemia

Abstract Introduction Maternal prenatal folate intake is associated with a decreased risk of acute lymphoblastic leukemia (ALL) in children. Genome-wide association studies (GWAS) show that variations in genes regulating folate metabolism impact serum folate level irrespective of nutritional intake. Polygenic risk scores (PRS) summarize the cumulative genetic liability associated with specific phenotypes. This study aimed to examine if the child PRS related to folate level interacts with maternal periconception folate intake from food and supplements, contributing to ALL risk. Methods Data on periconceptional folate intake spanning the year prior to pregnancy were obtained from the California Childhood Leukemia Study (CCLS). Folate intake from diet and supplement was measured in dietary folate equivalents (DFE). A PRS related to folate level was constructed using summary statistics from a GWAS of serum folate levels among Europeans. After assigning genetically predicted folate levels, odds ratios (ORs) and 95% confidence intervals (CIs) per 0.05 unit decrease of the folate PRS and per risk-associated T allele (at rs1801133 in the MTHFR gene) were estimated using logistic regression comparing ALL cases with controls, adjusted for child's age, sex, potential confounders, and ancestry principal components. Analyses were stratified by Latino and non-Latino Whites. Results We identified significant interactions between folate PRS/ rs1801133 and total folate from food in the Latino population, with interaction p-values of 0.008 and 0.005. The positive association between lower genetically predicted folate and ALL diminished with the increase in total folate intake from food. For folate PRS, ORs of ALL decreased from 1.32 (95% CI: 1.02-1.70) at 0 DFE, to 1.05 (95% CI: 0.93-1.20) at median intake (517.4 DFE), and to 0.54 (95% CI: 0.31-0.93) at maximum intake (2018.4 DFE). For the number of T allele at rs1801133, ORs decreased from 2.09 (95% CI: 1.19-3.68), to 1.05 (95% CI: 0.80-1.36), and to 0.14 (95% CI: 0.04-0.56). No interaction was found with folate from supplements. Additionally, lower folate PRS and T allele were shown to be positively associated with an increased risk of ALL among non-Latino Whites, regardless of folate intake from food or supplements, with ORs of 1.23 (95% CI: 1.08, 1.43) and 1.41 (95% CI: 1.04, 1.91), respectively. Conclusion Our findings underscore the critical role of dietary folate intake against ALL development within the Latino population, where increased folate intake appeared to mitigate the impact of genetic liability. In contrast, in CCLS non-Latino population, the risk of ALL associated with child genetic liability was independent of maternal folate intake. These results suggest that folate interventions tailored to genetic profiles may be effective for motivating improvements to nutrition status. Citation Format: Yijin Xiang, Catherine Metayer, Scott Kogan, Xiaomei Ma, Joseph Wiemels. The interrelationship between maternal periconception folate nutritional intake and child’s genetic liability in the etiology of childhood acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2281.