Association Between Folate Metabolites and the Development of Food Allergy in Children

Food allergy (FA) prevalence has increased within the past decades. Prior studies have postulated an association between folate exposure and the development of allergic disease. Folate is a water-soluble B vitamin involved in DNA methylation, a process that leads to heritable changes in gene expression. The principal folate involved in DNA methylation is 5-methyltetrahydrofolate (5-MTHF). Unmetabolized folic acid (UMFA) appears in circulation when the enzyme dihydrofolate reductase (DHFR), which converts folic acid to tetrahydrofolate, is saturated. The current study is the first to examine the association between UMFA and 5-MTHF and the development of food sensitization (FS) and FA.

This nested case control study retrospectively examined 1394 mother-infant pairs enrolled in the longitudinal Boston Birth Cohort. Folate measurements in maternal plasma or cord blood samples at the time of delivery, postnatal food-specific IgE measurements, and follow-up questionnaires regarding common food allergies were examined among studied dyads. Five hundred and seven children with FS and 78 with FA were identified.

Total folate, UMFA, and 5-MTHF were measured at birth and in early childhood. Food-specific IgE levels, clinical history, and dietary tolerance were used to classify children as FS, FA, or neither FS nor FA. Distributions of maternal, cord blood, and postnatal folate were examined by FS or FA outcomes in children. Folate concentrations were nonnormally distributed and were divided into quartiles. Multivariable logistic regression models were used to investigate the associations of folate forms with either FS or FA, adjusting for maternal age, race, education, history of atopy, smoking; child’s gender, mode of delivery, breastfeeding history, age at food-specific IgE measurement, and child’s age when clinical symptoms were assessed for patients with FA.

Mean total folate concentrations at birth were lower among patients who developed FA (30.2 vs 35.3 nmol/L). Mean concentrations of UMFA at birth were higher among patients who developed FA (1.7 vs 1.3 nmol/L). Higher quartiles of UMFA at birth were associated more strongly with FA. Neither early childhood concentrations of 5-MTHF nor UMFA were associated with development of FS or FA.

Higher concentrations of UMFA at birth were associated with development of FA. The authors question whether this may represent an unintended consequence of folic acid fortification and prenatal supplementation.

The United States mandated fortification of cereals and grains with folic acid in 1998 to prevent development of neural tube defects. Supplementation has resulted in increased circulation of UMFA, which is now seen in more than 95% of Americans. The authors acknowledge that the population within the current study is predominantly composed of individuals from a population with a higher prevalence of DHFR deletion, which may influence DHFR saturation and increase UFMA concentration. Additional study is needed to assess UFMA throughout pregnancy in various diverse populations, to optimize FA outcomes for children without incurring alternate risks.