Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes

Shorey‐Kendrick, Lyndsey E.; McEvoy, Cindy T.; O'Sullivan, Shannon M.; Milner, Kristin; Vuylsteke, Brittany; Tepper, Robert S.; Haas, David M.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.

doi:10.1186/s13148-021-01161-y

Cited by 24 publications

(23 citation statements)

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“…Likewise, RNF39 was found to be differentially methylated in a study of marijuana use 57 and other studies of smoking-related DNAm changes. 58,59 These findings add evidence for a select few biologically plausible genes whereby smoking may alter genetically driven gene regulation in NAc; additional evidence will require larger sample sizes to detect more subtle smoking-related effects.…”

Section: Discussionmentioning

confidence: 89%

Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci

Carnes,

Quach,

Zhou

et al. 2023

Preprint

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Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWAS) of smoking behaviors have identified hundreds of significant loci. Most GWAS-identified variants are noncoding with unknown neurobiological effects. We used genome-wide genotype, DNA methylation, and RNA sequencing data in postmortem human nucleus accumbens (NAc) to identifycis-methylation/expression quantitative trait loci (meQTLs/eQTLs), investigate variant-by-cigarette smoking interactions across the genome, and overlay QTL evidence at smoking GWAS-identified loci to evaluate their regulatory potential. Active smokers (N=52) and nonsmokers (N=171) were defined based on cotinine biomarker levels and next-of-kin reporting. We simultaneously tested variant and variant-by-smoking interaction effects on methylation and expression, separately, adjusting for biological and technical covariates and using a two-stage multiple testing approach with eigenMT and Bonferroni corrections. We found >2 million significant meQTL variants (padj<0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects; five meQTLs, mapping toNUDT12,FAM53B,RNF39, andADRA1B, showed a significant interaction with smoking. We found 57,683 significant eQTLs for 958 unique eGenes (padj<0.05) and no smoking interactions. Colocalization analyses identified loci with smoking-associated GWAS variants that overlapped meQTLs/eQTLs, suggesting that these heritable factors may influence smoking behaviors through functional effects on methylation/expression. One locus containingMUSTIN1andITIH4colocalized across all data types (GWAS + meQTL + eQTL). In this first genome-wide meQTL map in the human NAc, the enriched overlap with smoking GWAS-identified genetic loci provides evidence that gene regulation in the brain helps explain the neurobiology of smoking behaviors.

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Section: Discussionmentioning

confidence: 89%

Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci

Carnes,

Quach,

Zhou

et al. 2023

Preprint

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“…To more broadly assess EPIC and Custom array DNA methylation patterns, we compared the distributions of CpG β values across different tissues using available data for the EPIC array in DNA from airway epithelial cells (this study), airway smooth muscle cells (10), and buccal swabs, placenta cells, and cord blood (11), and for the Custom array in DNA from nasal epithelial cells and nasal lavage cells from URECA children, and buccal cells, cord blood cells, or placenta tissue from infants in the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) cohort (11). The β distributions were similar across cell sources for CpGs on the EPIC array ( Figure 3A ) but showed varying patterns between cell types on the Custom array ( Figure 3B ).…”

Section: Resultsmentioning

confidence: 99%

“…The nasal lavage cell DNA was isolated from URECA subjects around age 13 (mean = 13.4 years, range = 12.8 - 14.9 years) using the QIAamp DNA Micro Kit. The buccal, placenta and cord blood cell DNA was collected from 96 participants in the VCSIP cohort (11). Placental DNA was extracted from powdered tissue under liquid nitrogen, using the QIAcube for automated nucleic acid extraction.…”

Section: Methodsmentioning

confidence: 99%

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A Functional Genomics Pipeline to Identify High-Value Asthma and Allergy CpGs in the Human Methylome

Morin

Thompson

Helling

et al. 2022

Preprint

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DNA methylation of cytosines at CpG dinucleotides is a widespread epigenetic mark that is responsive to environmental exposures and associated with a wide range of human pathologies. However, compared to genetic variation, genome-wide epigenetic variation has been relatively unexplored due to the limited representation of variable CpGs on commercial high-throughput platforms. To address this gap, we developed a pipeline to identify high-value asthma- and allergy-associated CpGs among the >28 million CpG sites in the human genome. We focused on epithelial cells – sentinels in the airway that respond to inhaled microbes, pollution and allergens and mediate their downstream effects on asthma and allergic disease risk. We combined whole-genome bisulfite sequencing in these cells from children with and without allergic asthma and in silico evidence of functionality to identify high-value CpGs for a custom DNA methylation array. Compared to commercial arrays, the Asthma&Allergy Custom array was enriched for CpGs with intermediate methylation levels, which are more likely to be correlated with the expression of their nearest or target genes and associated with allergic sensitization in children of diverse ancestries compared to CpGs on the commercial array. Our study revealed signature features of functional CpGs and unveiled a wealth of DNA methylation variation at functional CpG sites that are missed by existing high-throughput arrays, indicating that inter-individual variation in DNA methylation may contribute more to disease risk than previously appreciated.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Significance StatementDNA methylation at CpG dinucleotides is a widespread epigenetic mark associated with both exposures and diseases, and with the expression of genes, in specific cell types. Yet, nearly all previous studies have been limited to the CpGs on commercial arrays, which represent <5% of the human methylome. We performed whole-genome bisulfite sequencing in airway epithelial cells from children with and without allergic asthma and used functional annotations of gene regulatory elements to design a custom Asthma&Allergy DNA methylation array. We identified signature features of high-value, functional CpGs that are associated with allergic sensitization and robust to ancestry. Our findings suggest that a large portion of the “functional” human methylome has been overlooked in previous epigenome-wide association studies.

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“…Furthermore, low intake of fruits, vegetables, juices, and vitamins (A, C, and E) was linked to deficits in lung function in children [ 96 ], and an association between low serum vitamin A levels and airway obstruction has been shown in healthy adults [ 97 ]. Because antioxidant enzymes are fundamental in the defense of the airways against oxidative stress, some proposed therapeutic strategies involve the intake of micronutrients such as vitamins (A, C, and E), polyphenols, and carotenoids to help protect (asthmatic) individuals from oxidative stress and airway inflammation [ 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ].…”

Section: Oxidative Stress and Inflammation In Asthmamentioning

confidence: 99%

Oxidative Stress and Inflammation in Acute and Chronic Lung Injuries

Bezerra

Lanzetti

Nesi³

et al. 2023

Antioxidants

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Acute and chronic lung injuries are among the leading causes of mortality worldwide. Lung injury can affect several components of the respiratory system, including the airways, parenchyma, and pulmonary vasculature. Although acute and chronic lung injuries represent an enormous economic and clinical burden, currently available therapies primarily focus on alleviating disease symptoms rather than reversing and/or preventing lung pathology. Moreover, some supportive interventions, such as oxygen and mechanical ventilation, can lead to (further) deterioration of lung function and even the development of permanent injuries. Lastly, sepsis, which can originate extrapulmonary or in the respiratory system itself, contributes to many cases of lung-associated deaths. Considering these challenges, we aim to summarize molecular and cellular mechanisms, with a particular focus on airway inflammation and oxidative stress that lead to the characteristic pathophysiology of acute and chronic lung injuries. In addition, we will highlight the limitations of current therapeutic strategies and explore new antioxidant-based drug options that could potentially be effective in managing acute and chronic lung injuries.

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Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes

Cited by 24 publications

References 94 publications

Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci

Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci

A Functional Genomics Pipeline to Identify High-Value Asthma and Allergy CpGs in the Human Methylome

Oxidative Stress and Inflammation in Acute and Chronic Lung Injuries

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