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Background <p>We previously reported improved respiratory outcomes in babies born to pregnant smokers supplemented with vitamin C (500&#xa0;mg/day) versus placebo in a randomized clinical trial. Improved respiratory outcomes persisted to 5&#xa0;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&amp;Allergy array enriched for asthma and allergy loci likely to have a functional impact on gene expression.</p> Results <p>We profiled DNAm at 36,999 CpGs in loci previously associated with asthma or allergic diseases using custom-content Asthma&amp;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 (FEF<sub>25-75</sub>) and (3) wheeze at 4–6&#xa0;years of age. We identified 9 genome-wide differentially methylated CpGs (DMCs; FDR &lt; 0.05) and 2 differentially methylated regions (DMRs) between vitamin C and placebo subjects and one CpG associated with FEF<sub>25-75</sub> 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 <i>SLC25A37</i> gene involved in mitochondrial iron transport.</p> Conclusions <p>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.</p> Clinical trial registration <p> ClinicalTrials.gov, NCT01723696 (Registered on November 6, 2011) and NCT03203603 (Registered on March 28, 2017).</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • 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

摘要

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).