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.

BACKGROUNDChronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV 1 ) over time. Yet it is possible that a normal decline in FEV 1 could also lead to COPD in persons whose maximally attained FEV 1 is less than population norms. METHODSWe stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV 1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV 1 over time among the participants according to their FEV 1 at cohort inception and COPD status at study end. RESULTSAmong 657 persons who had an FEV 1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV 1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV 1 before 40 years of age and had a rapid decline in FEV 1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV 1 in early adulthood and a subsequent mean decline in FEV 1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONSOur study suggests that low FEV 1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV 1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.) a bs tr ac t

Rationale: The effect of early life wheezing on respiratory function and continued symptoms through adolescence has not been fully described. Using data from a population-based birth cohort in Tucson, Arizona, we previously described four phenotypes based on the occurrence of wheezing lower respiratory illnesses before age 3 yr and active wheeze at age 6 yr: never wheezers (n ϭ 425), transient early wheezers (n ϭ 164), persistent wheezers (n ϭ 113), and lateonset wheezers (n ϭ 124). Objective: We sought to determine the prognosis for these phenotypes, with reference to lung function and symptoms, through adolescence. Methods: Current wheeze was assessed by questionnaire, lung function was measured by conventional spirometry, and atopy was determined by skin prick tests. Results: The prevalence of atopy and wheeze by age 16 yr was similar for never and transient wheezers and for persistent and late-onset wheezers. Both transient early, and persistent wheezers had significantly lower FEF 25-75 (-259 ml/s, p Ͻ 0.001, and -260 ml/s, p ϭ 0.001, respectively), FEV 1 (-75 ml, p ϭ 0.02, and -87 ml, p ϭ 0.03, respectively), and FEV 1 :FVC ratio (-1.9%, p ϭ 0.002, and -2.5%, p ϭ 0.001, respectively) through age 16 yr compared with never wheezers. Late-onset wheezers had levels of lung function similar to those of never wheezers through age 16 yr. There was no significant change in lung function among subjects with any of the four phenotypes, relative to their peers, from age 6 to 16 yr. Conclusion: Patterns of wheezing prevalence and levels of lung function are established by age 6 yr and do not appear to change significantly by age 16 yr in children who start having asthmalike symptoms during the preschool years.

Background-Together with smoking, the level of lung function attained in early adulthood is among the strongest predictors of chronic obstructive pulmonary disease. Whether airway function measured shortly after birth is a determinant of this level is currently unknown.

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Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone-both in the presence and absence of IgE sensitisation-suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases.

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Background-Recent studies have suggested that a restrictive pattern assessed with a single spirometry is associated with increased morbidity and mortality. In this study, we sought to determine demographic, clinical, and mortality profiles of subjects with either a recurrent or inconsistent restrictive spirometric pattern assessed prospectively.