DNA methylation at birth is associated with lung function development till age 26 years

Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25–75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBC-F2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

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Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood

Clinical Epigenetics ◽

10.1186/s13148-020-00992-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Shadia Khan Sunny ◽

Hongmei Zhang ◽

Fawaz Mzayek ◽

Caroline L. Relton ◽

Susan Ring ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Lung Function ◽

Lung Diseases ◽

Critical Role ◽

Enrichment Analysis ◽

Chronic Obstructive ◽

Chronic Lung Diseases ◽

Parents And Children ◽

Males And Females

Abstract Background The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood. Methods DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex. Results High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases. Conclusion The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.

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Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course

European Respiratory Journal ◽

10.1183/13993003.01795-2018 ◽

2019 ◽

Vol 53 (4) ◽

pp. 1801795 ◽

Cited By ~ 17

Author(s):

Herman T. den Dekker ◽

Kimberley Burrows ◽

Janine F. Felix ◽

Lucas A. Salas ◽

Ivana Nedeljkovic ◽

...

Keyword(s):

Gene Expression ◽

Lung Function ◽

Life Course ◽

Cord Blood ◽

Childhood Asthma ◽

Respiratory Health ◽

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

The Life Course

RationaleWe aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course.MethodsWe meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7–13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes.ResultsWe identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways.InterpretationOur findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

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Sex-specific longitudinal association of DNA methylation with lung function

ERJ Open Research ◽

10.1183/23120541.00127-2021 ◽

2021 ◽

pp. 00127-2021

Author(s):

Shadia Khan Sunny ◽

Hongmei Zhang ◽

Caroline L. Relton ◽

Susan Ring ◽

Latha Kadalayil ◽

...

Keyword(s):

Gene Expression ◽

Lung Function ◽

Mixed Models ◽

Enrichment Analysis ◽

Expression Data ◽

Specific Effects ◽

Parents And Children ◽

Longitudinal Association ◽

Males And Females ◽

Avon Longitudinal Study

Investigating whether DNA-M at an earlier age is associated with lung function at a later age and whether this relationship differs by sex could enable prediction of future lung function deficit.A training/testing-based technique was used to screen 402 714 cytosine-phosphate-guanine dinucleotide sites (CpGs) to assess the longitudinal association of blood-based DNA-M at ages 10 and 18-years with lung function at 18 and 26-years, respectively, in the Isle of Wight birth cohort (IOWBC). Multivariable linear mixed models were applied to the CpGs that passed screening. To detect differentially methylated regions (DMRs), DMR enrichment analysis was conducted. Findings were further examined in the Avon Longitudinal Study of Parents and Children (ALSPAC). Biological relevance of the identified CpGs was assessed utilizing gene expression data.DNA-M at 8 CpGs (FEV1: 5 and FEV1/FVC: 3 CpGs) at an earlier age was associated with lung function at a later age regardless of sex, while at 13 CpGs (FVC: 5, FEV1:3, and FEV1/FVC: 5 CpGs), the associations were sex-specific (pFDR<0.05) in IOWBC with consistent directions of association in ALSPAC (IOWBC-ALSPAC consistent CpGs). cg16582803 (WNT10A) and cg14083603 (ZGPAT) were replicated in ALSPAC for main and sex-specific effects, respectively. Among IOWBC-ALSPAC consistent CpGs, DNA-M at cg01376079 (SSH3) and cg07557690 (TGFBR3) was associated with gene expression both longitudinally and cross-sectionally. In total, 57 and 170 DMRs were linked to lung function longitudinally in males and females, respectively.CpGs showing longitudinal associations with lung function have the potential to serve as candidate markers in future studies on lung function deficit prediction.

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Smoking, DNA methylation and lung function: a Mendelian randomization analysis to investigate causal relationships

10.1101/19003335 ◽

2019 ◽

Author(s):

Emily Jamieson ◽

Roxanna Korologou-Linden ◽

Robyn E. Wootton ◽

Anna L. Guyatt ◽

Thomas Battram ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Mendelian Randomization ◽

Causal Effect ◽

Forced Expiratory Volume ◽

Multiple Trait ◽

Genome Wide ◽

Causal Variants ◽

Association Data ◽

Randomization Analysis

AbstractWhether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in one second (FEV1) in two-sample Mendelian randomization (MR) using methylation quantitative trait loci and genome-wide association data for FEV1. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p<1.2×10−4). Replication analysis supported a causal effect at three CpGs (cg21201401 (ZGPAT), cg19758448 (PGAP3) and cg12616487 (AHNAK) (p<0.0028). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites may influence lung function via effects on smoking. Using multiple-trait colocalization, we found evidence of shared causal variants between lung function, gene expression and DNA methylation. Findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although large, tissue-specific datasets are required to confirm these results.

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Lung function: population epidemiology and concordance in Australian children aged 11–12 years and their parents

BMJ Open ◽

10.1136/bmjopen-2018-023486 ◽

2019 ◽

Vol 9 (Suppl 3) ◽

pp. 53-62 ◽

Cited By ~ 4

Author(s):

Liam Welsh ◽

Gayan Kathriachchige ◽

Tahmeed Raheem ◽

Anneke C Grobler ◽

Melissa Wake ◽

...

Keyword(s):

Lung Function ◽

Population Sample ◽

Correlation Coefficients ◽

Cross Sectional Study ◽

Forced Expiratory Volume ◽

International Standards ◽

Linear Regression Models ◽

Cross Sectional ◽

Parents And Children ◽

Z Scores

ObjectivesTo describe the epidemiology of lung function in Australian children aged 11–12 years and their parents, and explore the degree of intergenerational concordance.DesignCross-sectional study (the Child Health CheckPoint) nested in the Longitudinal Study of Australian Children (LSAC).SettingAssessment centres in seven Australian cities and eight regional towns, February 2015 to March 2016. Families unable to attend a clinic appointment were offered a home visit during the same period.Participants1874 families (53% of all eligible) participated in the study. Lung function data were available for 1759 children aged 11–12 years and 1774 parents (1668 biological pairs).Outcome measuresParticipants completed spirometry with measures including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and mid expiratory flow (MEF), converted to z-scores using Global Lung Initiative equations. Parent–child concordance was assessed using Pearson’s correlation coefficients and multivariable linear regression models. Survey weights and methods accounted for LSAC’s complex sampling, stratification and clustering within postcodes.ResultsAll lung function measures followed approximately normal distributions. Mean (SD) for FEV1, FVC and MEF z-scores in children were 0.33 (1.07), 0.83 (1.14) and −0.48 (1.09), respectively. Mean (SD) in parents were 0.28 (1.10), 0.85 (1.15) and −0.45 (1.10), respectively. Parent FEV1, FVC and MEF were associated with child lung function with significant positive correlation coefficients (0.22, 95% CI 0.17 to 0.26; 0.24, 95% CI 0.20 to 0.29; and 0.24, 95% CI 0.20 to 0.29, respectively).ConclusionsMean lung volumes were larger but with smaller airway size than international standards for both parents and children in this population sample. Modest associations between parent and child lung function highlight the potential for better identification of ‘at risk’ populations. Therefore, these findings may aid the development of health policy that aims to prevent the onset or limit the progression of lung disease.

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Association of asthma and smoking with lung function impairment in adolescence and early adulthood: the Isle of Wight Birth Cohort Study

European Respiratory Journal ◽

10.1183/13993003.00477-2019 ◽

2019 ◽

Vol 55 (3) ◽

pp. 1900477 ◽

Cited By ~ 10

Author(s):

S. Hasan Arshad ◽

Claire Hodgekiss ◽

John W. Holloway ◽

Ramesh Kurukulaaratchy ◽

Wilfried Karmaus ◽

...

Keyword(s):

Lung Function ◽

Birth Cohort ◽

Smoking Status ◽

Early Adulthood ◽

Adult Life ◽

Population Based ◽

Forced Expiratory Volume ◽

Birth Cohort Study ◽

Irreversible Damage ◽

Isle Of Wight

We investigated associations of asthma and smoking with lung function and airway reversibility from childhood to early adulthood.The population-based Isle of Wight Birth Cohort (n=1456) was assessed at birth, and at 1, 2, 4, 10, 18 and 26 years. Asthma was defined as physician diagnosis plus current wheeze and/or treatment. Spirometry was conducted at 10 (n=981), 18 (n=839) and 26 years (n=547). Individuals were subdivided into nonsmokers without asthma, nonsmokers with asthma, smokers without asthma and smokers with asthma, based on asthma and smoking status at 26 years. Their lung function trajectories from 10 to 26 years were examined using longitudinal models.Nonsmokers with asthma had smaller forced expiratory volume in 1 s (FEV1), FEF25–75% (forced expiratory flow at 25–75% of forced vital capacity (FVC)) and FEV1/FVC ratio compared to nonsmokers without asthma at age 10 and 18 years, with differences reduced after bronchodilator (pre-bronchodilator FEV1 at 26 years 3.75 L versus 4.02 L, p<0.001; post-bronchodilator 4.02 L versus 4.16 L, p=0.08). This lung function deficit did not worsen after 18 years. Smokers without asthma had smaller FEF25–75% and FEV1/FVC ratio (but not FEV1) at 26 years compared to nonsmokers without asthma, with the deficit appearing after 18 years and persisting despite bronchodilator response (for FEV1/FVC ratio at 26 years 0.80 versus 0.81, p=0.002; post-bronchodilator 0.83 versus 0.85, p=0.005). Smokers with asthma had worse lung function compared to other groups.Lung function deficits associated with asthma and smoking occur early in life. They are not fully responsive to bronchodilators, indicating a risk for long-term lung health, which highlights the need to institute preventive measures in adolescence and early adult life before irreversible damage occurs.

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Passive Smoking by Asthmatics: Its Greater Effect on Boys Than on Girls and on Older Than on Younger Children

PEDIATRICS ◽

10.1542/peds.84.3.451 ◽

1989 ◽

Vol 84 (3) ◽

pp. 451-459 ◽

Cited By ~ 1

Author(s):

Andrew B. Murray ◽

Brenda J. Morrison

Keyword(s):

Lung Function ◽

Passive Smoking ◽

Vital Capacity ◽

Lung Function Test ◽

Asthma Severity ◽

Forced Expiratory Volume ◽

Test Results ◽

Asthmatic Children ◽

Function Test ◽

Forced Expiratory Flow

In 415 nonsmoking asthmatic children who were seen consecutively, asthma symptoms were more severe if the mother was a smoker than if she was a nonsmoker. This applied to both sexes but was more marked in boys than in girls. There were also other indications that sons were the more severely affected: the forced expiratory volume at 1 second, the forced expiratory flow rate during the middle half of the forced vital capacity, and the provocation concentration of histamine needed to result in a 20% decrease in the forced expiratory volume at 1 second were significantly decreased only in the sons, and lung function test results were significantly less in sons than in daughters of mothers who smoked. When the 415 children were stratified according to age, lung function improved significantly with increasing age in the children of nonsmokers; in children of smokers, by contrast, symptoms and lung function test results became progressively worse. As well, there was a correlation between these indications of asthma severity and the number of years the child had been exposed to the mother's smoke. It appeared that, compared with girls, boys were more sensitive to passive smoking, and that its adverse effect increased with age and with duration of exposure.

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Childhood wheezing phenotypes influence asthma, lung function and exhaled nitric oxide fraction in adolescence

European Respiratory Journal ◽

10.1183/13993003.00718-2015 ◽

2015 ◽

Vol 47 (2) ◽

pp. 510-519 ◽

Cited By ~ 22

Author(s):

Liesbeth Duijts ◽

Raquel Granell ◽

Jonathan A.C. Sterne ◽

A. John Henderson

Keyword(s):

Nitric Oxide ◽

Lung Function ◽

Latent Class ◽

Late Onset ◽

Population Based ◽

Forced Expiratory Volume ◽

Exhaled Nitric Oxide ◽

Mean Difference ◽

Lower Lung ◽

Forced Expiratory Flow

The objective of this study was to examine the associations of childhood wheezing phenotypes with asthma, lung function and exhaled nitric oxide fraction (FeNO) in adolescence.In a population-based, prospective cohort study of 6841 children, we used latent class analysis to identify wheezing phenotypes during the first 7 years of life. Physician-diagnosed asthma, spirometry and FeNO were assessed at 14–15 years.Compared with never/infrequent wheeze, intermediate-onset and persistent wheeze were consistently strongest associated with higher risk of asthma (risk ratio (95% CI) 10.9 (8.97–13.16) and 9.13 (7.74–10.77), respectively), lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (mean difference in standard deviation units (SDU) (95% CI) −0.34 (−0.54– −0.14) and −0.50 (−0.62– −0.38), respectively), lower forced expiratory flow at 25–75% of FVC (FEF25–75%) (mean difference in SDU (95% CI) −0.30 (−0.49– −0.10) and −0.42 (−0.54– −0.30), respectively) and increased FEV1 bronchodilator reversibility (mean difference in SDU (95% CI) 0.12 (0.02–0.22) and 0.13 (0.06–0.19), respectively). Prolonged early and persistent wheeze were associated with a decline in FEV1/FVC ratio and FEF25–75% between 8–9 and 14–15 years. Intermediate-onset, late-onset and persistent wheeze were associated with higher FeNO ratios (ratio of geometric means (95% CI) 1.90 (1.59–2.29), 1.57 (1.39–1.77) and 1.37 (1.22–1.53), respectively, compared with never/infrequent wheeze).Early-onset wheezing phenotypes persisting after 18 months of age show the strongest associations with asthma, lower lung function, even worsening from mid-childhood, and higher FeNO levels in adolescence.

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Dose–Response Relationship between Environmental Exposure to Nickel and Pulmonary Function in the Korean General Population Aged 40 or Older

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18137016 ◽

2021 ◽

Vol 18 (13) ◽

pp. 7016

Author(s):

Joon-Sung Joh ◽

Mo-Yeol Kang ◽

Jun-Pyo Myong

Keyword(s):

Lung Function ◽

General Population ◽

Pulmonary Function ◽

Dose Response ◽

Smoking Status ◽

Forced Expiratory Volume ◽

Function Impairment ◽

Forced Expiratory Flow ◽

Nickel Exposure ◽

The Relationship

Nickel is a well-known skin allergen; however, few studies to date have investigated the association between nickel exposure and lung function impairment. The present study, therefore, evaluated the relationship between blood nickel concentrations and lung function profiles in the Korean general population (n = 1,098). Dose–response relationships between blood nickel quartiles and pulmonary function were assessed by sex in multivariate models, after adjustment for potentially confounding factors such as age, height, and smoking status. Quartiles of blood nickel concentrations were significantly associated with markers of pulmonary function in Korean men, such as forced expiratory volume in 1 second (FEV1) and forced expiratory flow 25–75% (FEF25–75%). Relative to the first quartile, the estimated coefficients (standard error (SE)) of blood nickel levels for FEV1 in the third and fourth quartiles of Korean men were −126.6 mL (59.1) and −138.5 mL (59.8), respectively (p < 0.05). Relative to the first quartile, the estimated coefficients (SE) of blood nickel levels for FEF25–75% in the second and fourth quartiles were −244.9 mL (109.5) and −266.8 mL (111.5), respectively (p < 0.05). Dose–response relationships were observed between quartiles of blood nickel concentrations and the pulmonary function markers FEV1 and FEF25–75% in Korean men aged 40 or older.

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Higher serum 25(OH)D concentrations are associated with improved FEV1 and FVC in adolescence

European Respiratory Journal ◽

10.1183/13993003.01804-2016 ◽

2017 ◽

Vol 49 (4) ◽

pp. 1601804 ◽

Cited By ~ 7

Author(s):

Claudia Flexeder ◽

Elisabeth Thiering ◽

Sibylle Koletzko ◽

Dietrich Berdel ◽

Irina Lehmann ◽

...

Keyword(s):

Vitamin D ◽

Lung Function ◽

Structural Changes ◽

Forced Expiratory Volume ◽

Additive Models ◽

Birth Cohorts ◽

Mean Flow ◽

Flow Rates ◽

Hydroxyvitamin D ◽

Forced Expiratory Flow

Vitamin D plays a role in the development of the immune system and the lung, as well as in airway remodelling. Therefore, this study investigated the association between serum 25-hydroxyvitamin D (25(OH)D) concentrations and spirometric lung function parameters at age 15 years.In the German birth cohorts GINIplus and LISAplus, lung function testing by spirometry and 25(OH)D measurements were performed during the 15-year follow-up examinations. Valid lung function measurements pre- and/or post-bronchodilation and serum 25(OH)D concentrations, which were adjusted for the date of blood sampling to account for seasonal variability, were available for 2607 adolescents. Associations between 25(OH)D concentrations and spirometric parameters were analysed using generalised additive models adjusted for confounding factors.Serum 25(OH)D concentrations were significantly associated with forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC measured before bronchodilation after adjustment for potential confounders: FEV1 increased by 10 mL (95% CI 2–17), FVC by 20 mL (95% CI 12–28) and FEV1/FVC decreased by 0.177% (95% CI −0.286 to −0.067) per 10 nmol·L−1 increase in 25(OH)D concentrations. Flow rates (forced expiratory flow rates at 25, 50 and 75% of exhaled FVC (FEF25, FEF50, FEF75) and mean flow rate between 25 and 75% of FVC (FEF25–75)) were not associated with vitamin D. Similar associations were observed for lung function parameters measured after bronchodilation.Vitamin D concentrations are positively associated with volume-related lung function parameters pre- and post-bronchodilation, suggesting structural changes in peripheral airways.

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