Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls

Abstract

Background Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relationship by food sources versus folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known. Objectives We evaluated the relationship between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study. Methods Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n = 189) and controls (n = 205) in the California Childhood Leukemia Study (CCLS) from 1995–2008 was compared to periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term. Results Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n = 394). The top differentially methylated region at the promoter region of DUSP22 demonstrated DNA hypermethylation in ALL cases but not controls in response to total and food folate intake. We further identified eight interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and education level. Conclusions We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.

One-Carbon (Folate) Metabolism Pathway at Birth and Risk of Childhood Acute Lymphoblastic Leukemia: A Biomarker Study in Newborns

“…Alternatively, the timing of a potential impact of folate-related nutrients on blood cell development and epigenome at large in the fetus may occur in early pregnancy, as shown in studies of nutritionally deprived women during early pregnancy [42,43], although no studies to date have directly tested this yet for childhood leukemia. Our group has recently published results on the relationship of DNA methylation patterns associated with periconception folate intake in children with ALL vs. healthy controls [10]. This epigenome-wide association analysis revealed a differentially methylated region (DMR) in the promoter region of DUSP22, a protein phosphatase and known tumor suppressor, in response to total and food periconceptional folate intake.…”

“…Childhood ALL exhibits a peak in incidence at the age of 2-5 years, and several experiments have demonstrated that chromosomal abnormalities detected at diagnostic were also identified at birth (such as ETV6-RUNX1, RUNX1-RUNX1T1, and PML-RARA gene fusions, as well as high hyperdiploidy), providing strong support to the prenatal origin of many childhood leukemia subtypes [4][5][6][7][8]. In addition, a recent study on discordant twins for ALL supports a role for DNA methylation alterations in utero impacting leukemogenesis [9]; such DNA methylation patterns may be influenced by periconceptional nutrients including folate [10]. In epidemiologic studies using interview data, prenatal folic acid and vitamin intake from dietary sources and supplementation [11][12][13][14][15] has consistently emerged as a protective factor for childhood leukemia.…”

Expression Quantitative Trait Methylation Analysis Identifies Whole Blood Molecular Footprint in Fetal Alcohol Spectrum Disorder (FASD)

“…REEP3 (#609348 OMIM) encodes Receptor Accessory Protein 3 (REEP3), which belongs to the Receptor Expression Enhancing Proteins (REEP) family. A recent study showed an association between the DNAm of REEP3 at birth and periconceptional folate intake [ 12 ]. A DMR located in an intergenic region, downstream of REEP3 (chr10:65733092-65733575), was shown to be one of the ten most responsive DMRs to folate supplementation [ 12 ].…”

“…A recent study showed an association between the DNAm of REEP3 at birth and periconceptional folate intake [ 12 ]. A DMR located in an intergenic region, downstream of REEP3 (chr10:65733092-65733575), was shown to be one of the ten most responsive DMRs to folate supplementation [ 12 ]. While the DMR of the currently detected eQTM does not overlap directly, we hypothesize it could be highly relevant for FASD pathogenesis.…”

A Atenção Psicológica Ao Fim Da Vida No Contexto Dos Cuidados Paliativos

“…Esses resultados estão em consonância com estudo desenvolvido por Timms et al, (2019), no qual a suplementação de folato promoveu a hipometilação de uma variedade de loci gênicos, atuando como fator protetor. Nickels et al, (2022), encontrou resultados semelhantes indicando uma hipermetilação do DNA em casos de LLA em crianças de famílias de origem hispânica com renda e nível educacional mais baixos. Sugerindo que, uma menor ingestão de folato total e alimentar durante a gestação associa-se ao desenvolvimento de leucemia.…”