Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants.

Background: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes.

Objective: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations.

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.

VEGFA variants are associated with pre-school lung function, but not neonatal lung function.

Background: Vascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood.

Methods: We analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort.

Antibiotic use during pregnancy alters the commensal vaginal microbiota.

Antibiotics may induce alterations in the commensal microbiota of the birth canal in pregnant women. Therefore, we studied the effect of antibiotic administration during pregnancy on commensal vaginal bacterial colonization at gestational week 36. Six hundred and sixty-eight pregnant women from the novel unselected Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010 ) pregnancy cohort participated in this analysis.

Deep phenotyping of the unselected COPSAC2010 birth cohort study.

Background: We hypothesize that perinatal exposures, in particular the human microbiome and maternal nutrition during pregnancy, interact with the genetic predisposition to cause an abnormal immune modulation in early life towards a trajectory to chronic inflammatory diseases such as asthma and others.

Objective: The aim of this study is to explore these interactions by conducting a longitudinal study in an unselected cohort of pregnant women and their offspring with emphasis on deep clinical phenotyping, exposure assessment, and biobanking. Exposure assessments focus on the human microbiome.

Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates.

Rationale: The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children.

Objectives: To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life.

The PCDH1 gene and asthma in early childhood.

Previous studies have suggested that variants in the protocadherin-1 (PCDH1) gene, which is important for cell-cell adhesion, are associated with asthma, bronchial, hyperresponsiveness and atopic dermatitis in school children. Our aim was to associate common variants of the PCDH1 gene with longitudinally assessed asthma phenotypes and atopic dermatitis in early childhood. We analysed eight single-nucleotide polymorphisms in PCDH1 from 411 children born to asthmatic mothers from the Copenhagen Prospective Studies on Asthma in Childhood birth cohort.

[Childhood asthma: Danish guidelines for diagnosis and treatment].

These clinical guidelines were developed by the Danish Pediatric Asthma Center in collaboration with the Danish Paediatric Society. Key messages in the guidelines are: 1) Inhaled steroids are the most effective preventive medication and are first choice in children with persistent symptoms. 2) There is rarely indication for more than low to moderate doses of inhaled steroids as preventive medication.

Public hygiene campaign in denmark during the 2009 H1N1 pandemic had no effect on hospitalization rate of communicable diseases in children.

Background: During the 2009 H1N1 pandemic the Danish National board of Health carried out massive public hygiene campaigns to limit spread of disease. We aimed to investigate whether this resulted in lower incidences of communicable diseases in the paediatric population.

Methods: The study compared annual hospitalization rates for childhood infections from 2005 to 2011.

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B.

Objective assessment of levels and patterns of physical activity in preschool children.

Background: The aim of this study was to examine in detail levels and patterns of physical activity in preschool children and the effects of gender and BMI on this activity.

Methods: Two hundred and fifty-three children aged 5 y participating in the Copenhagen Prospective Studies on Asthma in Childhood wore an accelerometer day and night over a 4-wk period. The main outcome measure was level of physical activity using the raw data.

Association between whole-blood polyunsaturated fatty acids in pregnant women and early fetal weight.

Background/objectives: Studies suggest that intake of marine n-3 polyunsaturated fatty acids (n-3 PUFA) in pregnancy have an impact on birth weight, but only few have investigated the effect on early fetal growth. The objective of the study was to investigate the association between levels of PUFA in maternal blood in gestational week 24 and biometric measures and estimated fetal weight in gestational week 20.

Subjects/methods: In the COPSAC2010 cohort, whole-blood fatty acid composition (a biomarker of PUFA intake) from 583 women in week 24 was analyzed by gas chromatography.

Aerosol particle size does not predict pharmacokinetic determined lung dose in children.

In vitro measures of aerosol particles size, such as the fine particle mass, play a pivotal role for approval of inhaled anti-asthmatic drugs. However, the validity as a measure of dose to the lungs in children lacks evidence. In this study we investigated for the first time the association between an in vivo estimate of lung dose of inhaled drug in children and the corresponding particle size segments assessed ex vivo.

Rhinovirus wheezing illness and genetic risk of childhood-onset asthma.

Background: Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.

Methods: We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms.

Temporal mapping of CEBPA and CEBPB binding during liver regeneration reveals dynamic occupancy and specific regulatory codes for homeostatic and cell cycle gene batteries.

Dynamic shifts in transcription factor binding are central to the regulation of biological processes by allowing rapid changes in gene transcription. However, very few genome-wide studies have examined how transcription factor occupancy is coordinated temporally in vivo in higher animals. Here, we quantified the genome-wide binding patterns of two key hepatocyte transcription factors, CEBPA and CEBPB (also known as C/EBPalpha and C/EBPbeta), at multiple time points during the highly dynamic process of liver regeneration elicited by partial hepatectomy in mouse.

Pathogenic bacteria colonizing the airways in asymptomatic neonates stimulates topical inflammatory mediator release.

Rationale: Bacterial colonization of neonatal airways with the pathogenic bacterial species, Moraxella catarrhalis, Streptococcus pneumoniae, and Haemophilus influenzae, is associated with later development of childhood asthma.

Objectives: To study a possible association between colonization with pathogenic bacterial strains and the immune signature of the upper airways in healthy neonates.

Methods: A total of 20 cytokines and chemokines were quantified in vivo in the airway mucosal lining fluid of 662 neonates from the Copenhagen Prospective Study of Asthma in Childhood 2010 birth cohort.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking.

Fraction of exhaled nitric oxide and bronchial responsiveness are associated and continuous traits in young children independent of asthma.

Background: Elevated fraction of exhaled nitric oxide (FENO) and bronchial hyperresponsiveness are used as surrogate markers of asthma. These traits may be continuous in the population. The objective of this study was to investigate whether FENO and bronchial responsiveness are associated in both children with and children without a history of asthma symptoms.

Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study.

Background: Filaggrin null mutations result in impaired skin barrier functions, increase the risk of early onset atopic dermatitis and lead to a more severe and chronic disease. We aimed to characterize the clinical presentation and course of atopic dermatitis associated with filaggrin mutations within the first 7 years of life.

Method: The COPSAC cohort is a prospective, clinical birth cohort study of 411 children born to mothers with a history of asthma followed during their first 7 years of life with scheduled visits every 6 months, as well as visits for acute exacerbations of dermatitis.

Use of antibiotics during pregnancy increases the risk of asthma in early childhood.

Objectives: To investigate the hypothesis that mother's use of antibiotics in pregnancy could influence asthma and eczema in early life.

Study Design: Subjects were included from the Copenhagen Prospective Study on Asthma in Childhood cohort of children born of mothers with asthma (N = 411). Severe asthma exacerbations and eczema were diagnosed by research unit physicians.

Allergic rhinitis is associated with otitis media with effusion: a birth cohort study.

Background: Childhood otitis media with effusion is a common disease and a link to allergic diseases has been suggested.

Objective: To investigate the association between atopic disease and otitis media with effusion diagnosed according to strict objective case definitions by age 6 years.

Methods: We evaluated 291 children in the 6th year of life from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) 2000 birth cohort.