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.

The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. This multidisciplinary study focuses on several health outcomes including behaviour and cognition, body composition, eye development, growth, hearing, heart and vascular development, infectious disease and immunity, oral health and facial growth, respiratory health, allergy and skin disorders of children and their parents. Main exposures of interest include environmental, endocrine, genomic (genetic, epigenetic, microbiome), lifestyle related, nutritional and socio-demographic determinants. In total, 9778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Response at baseline was 61%, and general follow-up rates until the age of 10 years were around 80%. Data collection in children and their parents includes questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, lung function, Magnetic Resonance Imaging and biological sampling. Genome and epigenome wide association screens are available. Eventually, results from the Generation R Study contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 cases, 118,538 controls) from ethnically-diverse populations. We identified five new asthma loci, uncovered two additional novel associations at two known asthma loci, established asthma associations at two loci implicated previously in comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. Enrichment of asthma risk loci in enhancer marks, especially in immune cells, suggests a major role of these loci in the regulation of immune-related mechanisms.

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

WHAT'S KNOWN ON THIS SUBJECT:Exclusive breastfeeding seems to decrease the risk of infectious diseases in infancy. However, the World Health Organization has called for more research regarding the benefits for 6 months instead of 4 months of exclusive breastfeeding. WHAT THIS STUDY ADDS:Exclusive breastfeeding to the age of 6 months tended to be more protective than exclusive breastfeeding until the age of 4 months and partially thereafter. Our findings support health-policy strategies that promote exclusive breastfeeding for 6 months in industrialized countries. abstract OBJECTIVE: To examine the associations of duration of exclusive breastfeeding with infections in the upper respiratory (URTI), lower respiratory (LRTI), and gastrointestinal tracts (GI) in infancy. METHODS:This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward in the Netherlands. Rates of breastfeeding during the first 6 months (never; partial for Ͻ4 months, not thereafter; partial for 4 -6 months; exclusive for 4 months, not thereafter; exclusive for 4 months, partial thereafter; and exclusive for 6 months) and doctor-attended infections in the URTI, LRTI, and GI until the age of 12 months were assessed by questionnaires and available for 4164 subjects. RESULTS:Compared with never-breastfed infants, those who were breastfed exclusively until the age of 4 months and partially thereafter had lower risks of infections in the URTI, LRTI, and GI until the age of 6 months (adjusted odds ratio . Similar tendencies were observed for infants who were exclusively breastfed for 6 months or longer. Partial breastfeeding, even for 6 months, did not result in significantly lower risks of these infections. CONCLUSIONS:Exclusive breastfeeding until the age of 4 months and partially thereafter was associated with a significant reduction of respiratory and gastrointestinal morbidity in infants. Our findings support healthpolicy strategies to promote exclusive breastfeeding for at least 4 months, but preferably 6 months, in industrialized countries.

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BackgroundPreterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.ObjectivesWe performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).MethodsFirst, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.ResultsYounger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).ConclusionYounger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.

Atopic dermatitis (AD) is a common chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing AD are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 cases and 20,565 controls from 16 population-based cohorts and followed up the ten most strongly associated novel markers in a further 5,419 cases and 19,833 controls from 14 studies. Three SNPs met genome-wide significance in the discovery and replication cohorts combined: rs479844 upstream of OVOL1 (OR=0.88, p=1.1×10−13) and rs2164983 near ACTL9 (OR=1.16, p=7.1×10−9), genes which have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster on 5q31.1 (OR=1.11, p=3.8×10−8). We also replicated the FLG locus and two recently identified association signals at 11q13.5 (rs7927894, p=0.008) and 20q13.3 (rs6010620, p=0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in AD pathogenesis.