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Vitamin C supplementation to pregnant smokers alters asthma- and allergy-associated CpGs in child buccal DNA at 5 years of age.

  • 2025-10-03
  • Clinical epigenetics 17(1)
    • Lyndsey E Shorey-Kendrick
    • Cindy T McEvoy
    • Kristin Milner
    • Julia Harris
    • Julie Brownsberger
    • Robert S Tepper
    • Byung Park
    • Lina Gao
    • Annette Vu
    • Cynthia D Morris
    • Emma E Thompson
    • Carole Ober
    • Eliot R Spindel

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 137
Population
137 subjects (65 placebo; 72 vitamin C) with pulmonary function testing at the 5-year visit
Methods
Custom-content Asthma&Allergy array profiling DNAm at 36,999 CpGs; double-blind, placebo-controlled randomized clinical trial
Blinding
Double-blind
  • Large Human Trial

Background

We previously reported improved respiratory outcomes in babies born to pregnant smokers supplemented with vitamin C (500 mg/day) versus placebo in a randomized clinical trial. Improved respiratory outcomes persisted to 5 years of age and were associated with buccal DNA methylation (DNAm) measured using the InfiniumMethylationEPIC array. The objective of this study was to examine associations of vitamin C treatment and lung function with buccal DNAm using a custom-content Asthma&Allergy array enriched for asthma and allergy loci likely to have a functional impact on gene expression.

Results

We profiled DNAm at 36,999 CpGs in loci previously associated with asthma or allergic diseases using custom-content Asthma&Allergy arrays in 137 subjects (65 placebo; 72 vitamin C) with pulmonary function testing (PFT) at the 5-year visit in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" (VCSIP) double-blind, placebo-controlled randomized clinical trial. We examined the association of buccal DNAm with (1) vitamin C treatment vs placebo, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25-75) and (3) wheeze at 4-6 years of age. We identified 9 genome-wide differentially methylated CpGs (DMCs; FDR < 0.05) and 2 differentially methylated regions (DMRs) between vitamin C and placebo subjects and one CpG associated with FEF25-75 at FDR significance. DNAm at 5 CpGs mediated a significant proportion of the vitamin C treatment effect on lung function, including 2 CpGs annotated to the SLC25A37 gene involved in mitochondrial iron transport.

Conclusions

Our study revealed association of in utero vitamin C supplementation and childhood lung function with DNAm at novel loci, providing additional insight toward potential mechanisms for the persistent effects of vitamin C supplementation to pregnant smokers.

Clinical trial registration

ClinicalTrials.gov, NCT01723696 (Registered on November 6, 2011) and NCT03203603 (Registered on March 28, 2017).

Research Insights

  • Vitamin C→Improved Lung Function

    We identified 9 genome-wide differentially methylated CpGs (DMCs; FDR < 0.05) and 2 differentially methylated regions (DMRs) between vitamin C and placebo subjects and one CpG associated with FEF25-75 at FDR significance. DNAm at 5 CpGs mediated a significant proportion of the vitamin C treatment effect on lung function

    Effect
    Beneficial
    Effect size
    Moderate
    Dose
    500 mg/day
  • Vitamin C→Reduced Wheeze

    We examined the association of buccal DNAm with (1) vitamin C treatment vs placebo, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25-75) and (3) wheeze at 4-6 years of age.

    Effect
    Beneficial
    Effect size
    Small
    Dose
    500 mg/day
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