Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Distinction between rhinitis alone and rhinitis with asthma using interactomics.

The concept of "one-airway-one-disease", coined over 20 years ago, may be an over-simplification of the links between allergic diseases. Genomic studies suggest that rhinitis alone and rhinitis with asthma are operated by distinct pathways. In this MeDALL (Mechanisms of the Development of Allergy) study, we leveraged the information of the human interactome to distinguish the molecular mechanisms associated with two phenotypes of allergic rhinitis: rhinitis alone and rhinitis in multimorbidity with asthma. We observed significant differences in the topology of the interactomes and in the pathways associated to each phenotype. In rhinitis alone, identified pathways included cell cycle, cytokine signalling, developmental biology, immune system, metabolism of proteins and signal transduction. In rhinitis and asthma multimorbidity, most pathways were related to signal transduction. The remaining few were related to cytokine signalling, immune system or developmental biology. Toll-like receptors and IL-17-mediated signalling were identified in rhinitis alone, while IL-33 was identified in rhinitis in multimorbidity. On the other hand, few pathways were associated with both phenotypes, most being associated with signal transduction pathways including estrogen-stimulated signalling. The only immune system pathway was FceRI-mediated MAPK activation. In conclusion, our findings suggest that rhinitis alone and rhinitis and asthma multimorbidity should be considered as two distinct diseases.

Effect of residential relocation on environmental exposures in European cohorts: An exposome-wide approach.

Residential relocation is increasingly used as a natural experiment in epidemiological studies to assess the health impact of changes in environmental exposures. Since the likelihood of relocation can be influenced by individual characteristics that also influence health, studies may be biased if the predictors of relocation are not appropriately accounted for. Using data from Swedish and Dutch adults (SDPP, AMIGO), and birth cohorts (BAMSE, PIAMA), we investigated factors associated with relocation and changes in multiple environmental exposures across life stages. We used logistic regression to identify baseline predictors of moving, including sociodemographic and household characteristics, health behaviors and health. We identified exposure clusters reflecting three domains of the urban exposome (air pollution, grey surface, and socioeconomic deprivation) and conducted multinomial logistic regression to identify predictors of exposome trajectories among movers. On average, 7 % of the participants relocated each year. Before relocating, movers were consistently exposed to higher levels of air pollution than non-movers. Predictors of moving differed between the adult and birth cohorts, highlighting the importance of life stages. In the adult cohorts, moving was associated with younger age, smoking, and lower education and was independent of cardio-respiratory health indicators (hypertension, BMI, asthma, COPD). Contrary to adult cohorts, higher parental education and household socioeconomic position were associated with a higher probability of relocation in birth cohorts, alongside being the first child and living in a multi-unit dwelling. Among movers in all cohorts, those with a higher socioeconomic position at baseline were more likely to move towards healthier levels of the urban exposome. We provide new insights into predictors of relocation and subsequent changes in multiple aspects of the urban exposome in four cohorts covering different life stages in Sweden and the Netherlands. These results inform strategies to limit bias due to residential self-selection in epidemiological studies using relocation as a natural experiment.

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Air pollution exposure impairs lung function in infants.

AIM: To assess associations between air pollution exposure and infant lung function. METHODS: Healthy infants from Stockholm were recruited to two cohorts (n = 99 and n = 78). Infant spirometry included plethysmography and raised volume forced expiratory flows. In pooled analyses, lung function at ~6 months of age was related to time-weighted average air pollution levels at residential addresses from birth until the lung function test. The pollutants included particulate matter with an aerodynamic diameter < 10 µm (PM10 ) or <2.5 µm and nitrogen dioxide. RESULTS: There were significant inverse relations between air pollution exposure during infancy and forced expiratory volume at 0.5 s (FEV0.5 ) as well as forced vital capacity (FVC) for all pollutants. For example, the decline was 10.1 ml (95% confidence interval 1.3-18.8) and 10.3 ml (0.5-20.1) in FEV0.5 and FVC, respectively, for an interquartile increment of 5.3 µg/m3 in PM10 . Corresponding associations for minute ventilation and functional residual capacity were 43.3 ml/min (-9.75-96.3) and 0.84 ml (-4.14-5.82). CONCLUSIONS: Air pollution exposure was associated with impaired infant lung function measures related to airway calibre and lung volume, suggesting that comparatively low levels of air pollution negatively affect lung function in early life.

Association of Short-term Air Pollution Exposure With SARS-CoV-2 Infection Among Young Adults in Sweden.

Importance: Mounting ecological evidence shows an association between short-term air pollution exposure and COVID-19, yet no study has examined this association on an individual level. Objective: To estimate the association between short-term exposure to ambient air pollution and SARS-CoV-2 infection among Swedish young adults. Design, Setting, and Participants: This time-stratified case-crossover study linked the prospective BAMSE (Children, Allergy Milieu, Stockholm, Epidemiology [in Swedish]) birth cohort to the Swedish national infectious disease registry to identify cases with positive results for SARS-CoV-2 polymerase chain reaction (PCR) testing from May 5, 2020, to March 31, 2021. Case day was defined as the date of the PCR test, whereas the dates with the same day of the week within the same calendar month and year were selected as control days. Data analysis was conducted from September 1 to December 31, 2021. Exposures: Daily air pollutant levels (particulate matter with diameter ≤2.5 µm [PM2.5], particulate matter with diameter ≤10 µm [PM10], black carbon [BC], and nitrogen oxides [NOx]) at residential addresses were estimated using dispersion models with high spatiotemporal resolution. Main Outcomes and Measures: Confirmed SARS-CoV-2 infection among participants within the BAMSE cohort. Distributed-lag models combined with conditional logistic regression models were used to estimate the association. Results: A total of 425 cases were identified, of whom 229 (53.9%) were women, and the median age was 25.6 (IQR, 24.9-26.3) years. The median exposure level for PM2.5 was 4.4 [IQR, 2.6-6.8] µg/m3 on case days; for PM10, 7.7 [IQR, 4.6-11.3] µg/m3 on case days; for BC, 0.3 [IQR, 0.2-0.5] µg/m3 on case days; and for NOx, 8.2 [5.6-14.1] µg/m3 on case days. Median exposure levels on control days were 3.8 [IQR, 2.4-5.9] µg/m3 for PM2.5, 6.6 [IQR, 4.5-10.4] µg/m3 for PM10, 0.2 [IQR, 0.2-0.4] µg/m3 for BC, and 7.7 [IQR, 5.3-12.8] µg/m3 for NOx. Each IQR increase in short-term exposure to PM2.5 on lag 2 was associated with a relative increase in positive results of SARS-CoV-2 PCR testing of 6.8% (95% CI, 2.1%-11.8%); exposure to PM10 on lag 2, 6.9% (95% CI, 2.0%-12.1%); and exposure to BC on lag 1, 5.8% (95% CI, 0.3%-11.6%). These findings were not associated with NOx, nor were they modified by sex, smoking, or having asthma, overweight, or self-reported COVID-19 respiratory symptoms. Conclusions and Relevance: The findings of this case-crossover study of Swedish young adults suggest that short-term exposure to particulate matter and BC was associated with increased risk of positive PRC test results for SARS-CoV-2, supporting the broad public health benefits of reducing ambient air pollution levels.

Assessment of chronic bronchitis and risk factors in young adults: results from BAMSE.

BACKGROUND: Chronic bronchitis is associated with substantial morbidity among elderly adults, but little is known about its prevalence and risk factors in young adults. Our aim was to assess the prevalence and early-life risk factors for chronic bronchitis in young adults. METHODS: Questionnaire data and clinical measures from the 24-year follow-up of the Swedish BAMSE (Child (Barn), Allergy, Milieu, Stockholm, Epidemiological) cohort were used. We assessed chronic bronchitis (CB) as the combination of cough and mucus production in the morning during winter. Environmental and clinical data from birth and onwards were used for analyses of risk factors. RESULTS: At the 24-year follow-up, 75% (n=3064) participants completed the questionnaire and 2030 performed spirometry. The overall prevalence of CB was 5.5% (n=158) with similar estimates in males and females. 49% of CB cases experienced more than three self-reported respiratory infections in the past year compared to 18% in non-CB subjects (p<0.001), and 37% of cases were current smokers (versus 19% of non-CB cases). Statistically significant lower post-bronchodilator forced expiratory volume in 1 s/forced vital capacity were observed in CB compared to non-CB subjects (mean z-score -0.06 versus 0.13, p=0.027). Daily smoking (adjusted (a)OR 3.85, p<0.001), air pollution exposure (black carbon at ages 1-4 years aOR 1.71 per 1 µg·m-3 increase, p=0.009) and exclusive breastfeeding for ≤4 months (aOR 0.66, p=0.044) were associated with CB. CONCLUSION: Chronic bronchitis in young adults is associated with recurrent respiratory infections. Besides smoking, our results support the role of early-life exposures, such as air pollution and exclusive breastfeeding, for respiratory health later in life.

Maternal Smoking during Pregnancy and Early Childhood and Development of Asthma and Rhinoconjunctivitis - a MeDALL Project.

BACKGROUND: The role of tobacco smoke exposure in the development and persistence of asthma and rhinoconjunctivitis through childhood into adolescence is unclear. OBJECTIVES: We assessed the associations of parental smoking from fetal life through adolescence with asthma and rhinoconjunctivitis during childhood and adolescence. METHODS: We analyzed data for 10,860 participants of five European birth cohort studies from the Mechanisms of the Development of Allergy (MeDALL) consortium. Parental smoking habits and health outcomes (early transient, persistent, and adolescent-onset asthma and rhinoconjunctivitis) were based on questionnaires covering the period from pregnancy to 14-16 y of age. Data were combined and analyzed using a one-stage and two-stage individual participant data meta-analysis. RESULTS: Overall, any maternal smoking during pregnancy tended to be associated with an increased odds of prevalent asthma [adjusted odds ratio (aOR)=1.19 (95% CI: 0.98, 1.43)], but not prevalent rhinoconjunctivitis [aOR=1.05 (95% CI: 0.90, 1.22)], during childhood and adolescence. In analyses with phenotypes related to age of onset and persistence of disease, any maternal smoking during pregnancy was associated with early transient asthma [aOR=1.79 (95% CI: 1.14, 2.83)]. Maternal smoking of ≥10 cigarettes/day during pregnancy was associated with persistent asthma [aOR=1.66 (95% CI: 1.29, 2.15)] and persistent rhinoconjunctivitis [aOR=1.55 (95% CI, 1.09, 2.20)]. Tobacco smoke exposure during fetal life, infancy, childhood, and adolescence was not associated with adolescent-onset asthma or rhinoconjunctivitis. CONCLUSIONS: Findings from this combined analysis of five European birth cohorts strengthen evidence linking early exposure to tobacco smoke with asthma during childhood and adolescence. Children with high early-life exposure were more likely than unexposed children to have early transient and persistent asthma and persistent rhinoconjunctivitis. https://doi.org/10.1289/EHP2738.

Combined effects of multiple risk factors on asthma in school-aged children.

BACKGROUND: Little is known about synergistic effects of several risk factors on asthma. We developed a risk score in Puerto Rican children, and then used this score to estimate the combined effects of multiple risk factors on asthma at school age in Puerto Rican and Swedish children. METHODS: Case-control study in 609 Puerto Rican children (aged 6-14 years) and longitudinal birth cohort study of 2290 Swedish children followed up to age 12 years (The Children, Allergy, Milieu, Stockholm, Epidemiological Survey [BAMSE] Study). In both cohorts, there was data on parental asthma, sex, obesity, allergic rhinitis, and early-life second-hand smoke (SHS); data on diet and (in children ≥9 years) lifetime exposure to gun violence were also available in the Puerto Rico study. Asthma was defined as physician-diagnosed asthma and ≥1 episode of wheeze in the previous year. RESULTS: In a multivariable analysis in Puerto Rican children, male sex, parental asthma, allergic rhinitis, early-life SHS, an unhealthy diet and (in children ≥9 years) gun violence were each significantly associated with asthma. We next created a risk score using these variables (range, 0 to 5-6 in Puerto Rico and 0 to 4 in BAMSE). Compared with Puerto Rican children without any risk factors (i.e. a score of 0), Puerto Rican children with 2, 3, and at least 4 risk factors had 3.6 times (95% CI = 1.4-9.2), 10.4 times (95% CI = 4.0-27.0), and 21.6 times (95% CI = 7.2-64.9) significantly higher odds of asthma, respectively. In BAMSE, the presence of 2, 3, and at least 4 risk factors was significantly associated with 4.1 times (95% CI = 2.3-7.4), 6.3 times (95% CI = 3.0-13.3), and 17.2 times (95% CI = 4.1-73.2) increased odds of asthma at age 12 years. CONCLUSIONS: Our findings emphasize the multifactorial etiology of asthma, and suggest that concurrent eradication or reduction of several modifiable risk factors may better prevent or reduce the burden of childhood asthma.

Exposure to Traffic-Related Air Pollution and Serum Inflammatory Cytokines in Children.

BACKGROUND: Long-term exposure to ambient air pollution can lead to adverse health effects in children; however, underlying biological mechanisms are not fully understood. OBJECTIVES: We evaluated the effect of air pollution exposure during different time periods on mRNA expression as well as circulating levels of inflammatory cytokines in children. METHODS: We measured a panel of 10 inflammatory markers in peripheral blood samples from 670 8-y-old children in the Barn/Child, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) birth cohort. Outdoor concentrations of nitrogen dioxide (NO2) and particulate matter (PM) with aerodynamic diameter <10 µm (PM10) from road traffic were estimated for residential, daycare, and school addresses using dispersion modeling. Time-weighted average exposures during infancy and at biosampling were linked to serum cytokine levels using linear regression analysis. Furthermore, gene expression data from 16-year-olds in BAMSE (n=238) were used to evaluate links between air pollution exposure and expression of genes coding for the studied inflammatory markers. RESULTS: A 10 µg/m3 increase of NO2 exposure during infancy was associated with a 13.6% (95% confidence interval (CI): 0.8; 28.1%) increase in interleukin-6 (IL-6) levels, as well as with a 27.8% (95% CI: 4.6, 56.2%) increase in IL-10 levels, the latter limited to children with asthma. However, no clear associations were observed for current exposure. Results were similar using PM10, which showed a high correlation with NO2. The functional analysis identified several differentially expressed genes in response to air pollution exposure during infancy, including IL10, IL13, and TNF;. CONCLUSION: Our results indicate alterations in systemic inflammatory markers in 8-y-old children in relation to early-life exposure to traffic-related air pollution. https://doi.org/10.1289/EHP460.

Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up.

RATIONALE: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. OBJECTIVES: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. METHODS: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. MEASUREMENTS AND MAIN RESULTS: In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc ß-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. CONCLUSIONS: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Early-Life Exposure to Traffic-related Air Pollution and Lung Function in Adolescence.

RATIONALE: Exposure to air pollution during infancy has been related to lung function decrements in 8-year-old children, but whether the negative effects remain into adolescence is unknown. OBJECTIVES: To investigate the relationship between long-term air pollution exposure and lung function up to age 16 years. METHODS: A total of 2,278 children from the Swedish birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) performed spirometry at age 16 years. Levels of outdoor air pollution from local road traffic were estimated (nitrogen oxides [NOx] and particulate matter with an aerodynamic diameter of <10 µm [PM10]) for residential, daycare, and school addresses during the lifetime using dispersion modeling. Associations between exposure in different time windows and spirometry indexes were analyzed by linear regression and mixed effect models. MEASUREMENTS AND MAIN RESULTS: Exposure to traffic-related air pollution during the first year of life was associated with FEV1 at age 16 years of -15.8 ml (95% confidence interval [CI], -33.6 to 2.0 for a 10 µg/m(3) difference in NOx), predominately in males (-30.4 ml; 95% CI, -59.1 to -1.7), and in subjects not exposed to maternal smoking during pregnancy or infancy. Later exposures appeared to have had an additional negative effect. High exposure during the first year of life was also associated with odds ratios for FEV1 and FVC less than the lower limit of normal (LLN) (defined as a z-score < -1.64 SD) of 3.8 (95% CI, 1.3-10.9) and of 4.3 (95% CI, 1.2-15.0), respectively. The results for PM10 were similar to those for NOx. CONCLUSIONS: Exposure to traffic-related air pollution in infancy is negatively associated with FEV1 at age 16 years, leading to increased risk of clinically important deficits.

Pre- and postnatal exposure to parental smoking and allergic disease through adolescence.

OBJECTIVES: To examine the role of prenatal and postnatal second-hand tobacco smoke (SHS) exposure on asthma, rhinitis, and eczema development up to 16 years of age. METHODS: A birth cohort of 4089 children was followed for 16 years. Information on parental smoking habits, lifestyle factors, and symptoms of allergic disease was gathered using repeated parental questionnaires. Generalized estimating equations assessed the overall and age-specific associations between SHS exposure and allergic disease at ages 1 to 16 years. RESULTS: Exposure to SHS in utero was associated with an overall elevated risk of developing asthma up to 16 years (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.15-1.83) but not for rhinitis or eczema. After additional adjustment for parental smoking throughout childhood, excess overall risks for asthma remained statistically significant. Moreover, a dose-dependent pattern with SHS was observed. Exposure to SHS during infancy was associated with an overall elevated risk of asthma (OR = 1.23; 95% CI, 1.01-1.51), rhinitis (OR = 1.18; 95% CI, 1.01-1.39), and eczema (OR = 1.26; 95% CI, 1.09-1.45) up to 16 years. When age-specific associations were examined, the elevated risks related to SHS exposure in utero or during infancy were mostly confined to early childhood for asthma and rhinitis, whereas the excess risk of eczema appeared greatest at later ages. CONCLUSIONS: Our findings indicate that early SHS exposure, in utero or during infancy, influences the development of allergic disease up to adolescence. Excess risks for asthma and rhinitis were seen primarily in early childhood, whereas those for eczema occurred at later ages.

An update on epigenetics and childhood respiratory diseases.

Epigenetic mechanisms, defined as changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence, have been proposed to constitute a link between genetic and environmental factors that affect complex diseases. Recent studies show that DNA methylation, one of the key epigenetic mechanisms, is altered in children exposed to air pollutants and environmental tobacco smoke early in life. Several candidate gene studies on epigenetics have been published to date, but it is only recently that global methylation analyses have been performed for respiratory disorders such as asthma and chronic obstructive pulmonary disease. However, large-scale studies with adequate power are yet to be presented in children, and implications for clinical use remain to be evaluated. In this review, we summarize the recent advances in epigenetics and respiratory disorders in children, with a main focus on methodological challenges and analyses related to phenotype and exposure using global methylation approaches.