Shorey-Kendrick Lyndsey E, McEvoy Cindy T, Milner Kristin, Harris Julia, Brownsberger Julie, Tepper Robert S, Park Byung, Gao Lina, Vu Annette, Morris Cynthia D, Thompson Emma E, Ober Carole, Spindel Eliot R
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave, Beaverton, OR, 97006, USA.
Department of Pediatrics, Pape Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.
Clin Epigenetics. 2025 Oct 3;17(1):155. doi: 10.1186/s13148-025-01965-2.
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.
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 (FEF) 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 FEF 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.
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.
ClinicalTrials.gov, NCT01723696 (Registered on November 6, 2011) and NCT03203603 (Registered on March 28, 2017).
我们之前在一项随机临床试验中报告称，与服用安慰剂的孕妇吸烟者所生婴儿相比，补充维生素C（500毫克/天）的孕妇吸烟者所生婴儿的呼吸结局得到改善。呼吸结局的改善持续至5岁，并且与使用InfiniumMethylationEPIC芯片检测的颊黏膜DNA甲基化（DNAm）有关。本研究的目的是使用定制内容的哮喘与过敏芯片，该芯片富集了可能对基因表达有功能影响的哮喘和过敏相关位点，来研究维生素C治疗和肺功能与颊黏膜DNAm之间的关联。
在“维生素C减轻孕期吸烟对婴儿肺功能的影响”（VCSIP）双盲、安慰剂对照随机临床试验中，我们在137名受试者（65名服用安慰剂；72名补充维生素C）中，使用定制内容的哮喘与过敏芯片对36,999个与哮喘或过敏性疾病相关位点的CpG进行了甲基化分析，并在5岁随访时进行了肺功能测试（PFT）。我们研究了颊黏膜DNAm与以下因素的关联：（1）维生素C治疗与安慰剂；（2）呼出容积25%至75%之间的用力呼气流量（FEF）；（3）4至6岁时的喘息。我们在维生素C组和安慰剂组受试者之间鉴定出9个全基因组差异甲基化CpG（DMC；FDR<0.05）和2个差异甲基化区域（DMR），以及1个在FDR显著性水平下与FEF相关的CpG。5个CpG的DNAm介导了维生素C治疗对肺功能的很大一部分影响，其中包括2个注释到参与线粒体铁转运的SLC25A37基因的CpG。
我们的研究揭示了宫内补充维生素C和儿童肺功能与新位点的DNAm之间的关联，为孕期吸烟者补充维生素C的持续影响的潜在机制提供了更多见解。
ClinicalTrials.gov，NCT01723696（于2011年11月6日注册）和NCT03203603（于2017年3月28日注册）。
