Abstract:Rationale:
Poor lung health in adult life may occur partly through
suboptimal growth and development, as suggested by epidemiological evidence
pointing to early life risk factors.
Objectives:
To systematically investigate the effects of lung
development genes on adult lung function.
Methods:
Using UK Biobank data, we tested the association of 391
genes known to influence lung development with FVC and FEV
1
/FVC. We
split the data… Show more
“…We also identified 30 genes annotated to CpGs associated with FEF 75 with known roles in lung development, including 6 genes ( ROR2, SOX9, GATA6, RUNX2, RUNX3, and ACTN4 ) previously associated with adult lung function (Fig. 4 ; Additional file 2 : Table S2) [ 61 ]. The top CpG among candidates associated with FEF 75 was cg03172077, annotated to TOP3B (Fig.…”
Section: Resultsmentioning
confidence: 99%
“… Fig. 4 Overlap of genes containing restored DMRs and candidate loci nominally associated with respiratory outcomes (12 month FEF 75 and/or composite wheeze score) and candidate lung development genes [ 61 ] Fig. 5 Top CpGs associated with a 12 month FEF 75 and b composite wheeze score …”
Section: Resultsmentioning
confidence: 99%
“…Eighteen wheeze associated CpGs in placenta annotated to 14 unique genes with known roles in lung development (Fig. 4 ; Additional file 2 : Table S2) [ 61 ]. The top (and only FDR significant) CpG associated with wheeze was cg26433839, annotated to PRKCA, in addition to 47 PRKCA CpGs and 6 CpGs annotated to APOH (directly upstream of PRKCA) found to have nominally significant lower methylation associated with wheeze (Fig.…”
Background
Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes.
Results
DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate “restored CpGs” for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers.
Conclusions
Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP.
Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696.
“…We also identified 30 genes annotated to CpGs associated with FEF 75 with known roles in lung development, including 6 genes ( ROR2, SOX9, GATA6, RUNX2, RUNX3, and ACTN4 ) previously associated with adult lung function (Fig. 4 ; Additional file 2 : Table S2) [ 61 ]. The top CpG among candidates associated with FEF 75 was cg03172077, annotated to TOP3B (Fig.…”
Section: Resultsmentioning
confidence: 99%
“… Fig. 4 Overlap of genes containing restored DMRs and candidate loci nominally associated with respiratory outcomes (12 month FEF 75 and/or composite wheeze score) and candidate lung development genes [ 61 ] Fig. 5 Top CpGs associated with a 12 month FEF 75 and b composite wheeze score …”
Section: Resultsmentioning
confidence: 99%
“…Eighteen wheeze associated CpGs in placenta annotated to 14 unique genes with known roles in lung development (Fig. 4 ; Additional file 2 : Table S2) [ 61 ]. The top (and only FDR significant) CpG associated with wheeze was cg26433839, annotated to PRKCA, in addition to 47 PRKCA CpGs and 6 CpGs annotated to APOH (directly upstream of PRKCA) found to have nominally significant lower methylation associated with wheeze (Fig.…”
Background
Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes.
Results
DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate “restored CpGs” for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers.
Conclusions
Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP.
Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696.
“…Both cognition and lung function follow life course trajectories, influenced by a combination of genetic and life course factors [4]. Genetic determinants of lung development and disease are increasingly recognised [31]. In addition to shared environmental risk for lung function and cognitive function, shared genetic risks may be found.…”
Background
Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR).
Methods
Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates.
Results
We found only weak evidence that reduced lung function (Beta − 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (− 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV1 and FVC do cause lower cognitive function, but that after conditioning for height (− 0.03 (0.03), p-value 0.29 and − 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (− 0.03 (0.03) p-value 0.33 and − 0.01 (0.02), p-value 0.35) the evidence became weak.
Conclusion
We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.
“…In this context, Portas and colleagues (pp. 853–865 ) report in this issue of the Journal associations between lung developmental genes and adult lung function using the U.K. Biobank ( 5 ). They make use of lung development biology knowledge, selecting candidate genes to explore associations with lung function indices ( Figure 1 ), rather than starting with an agnostic genome-wide association study (GWAS) analysis, currently a standard approach.…”
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