Search

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

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Objective: Asthma is a common chronic respiratory airway disease influenced by environmental factors and possibly their interaction with the human genome causing epigenetic changes. Epigenome-wide association studies (EWAS) have mainly investigated DNA methylation and its association with disease or traits, exposure factors or gene expression. This systematic review aimed to identify all EWAS assessing differentially methylated sites associated with asthma in humans., Design: Structured systematic literature search following PRISMA guidelines, Newcastle-Ottawa Scale (NOS) for cohort studies was used for bias assessment., Data Sources: We searched PubMed and Embase databases from 2005 to 2019., Eligibility Criteria: Epigenome-wide association studies testing association between differential methylation and asthma in humans., Results: Overall, we identified 16 EWAS studies complying with our search criteria. Twelve studies were conducted on children, and 10 were conducted on sample sizes <150 subjects. Four hundred and nineteen CpGs were reported in children studies after correction for multiple testing. In the adult studies, thousands of differentially methylated sites were identified. Differential methylation in inflammatory-related genes correlated with higher levels of gene expressions of inflammatory modulators in asthma. Differentially methylated genes associated with asthma included SMAD3, SERPINC1, PROK1, IL13, RUNX3 and TIGIT. Forty-one CpGs were replicated at least once in blood samples, and 28 CpGs were replicated in nasal samples., Conclusion: Although many differentially methylated CpGs in genes known to be involved in asthma have been identified in EWAS to date, we conclude that further studies of larger sample sizes and analyses of differential methylation between different phenotypes are needed in order to comprehensively evaluate the role of epigenetic factors in the pathophysiology and heterogeneity of asthma, and the potential clinical utility to predict or classify patients with asthma., (© 2019 John Wiley & Sons Ltd.)

Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis., Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma., Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions., Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2., Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium., (Published by Elsevier Inc.)

Background: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes., Objectives: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children., Methods: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression., Results: Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns., Conclusions: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.

Rationale: We 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., Methods: We 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 (FEV 1 ), FEV 1 /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., Results: We 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., Interpretation: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course., Competing Interests: Conflict of interest: H.T. den Dekker has nothing to disclose. Conflict of interest: K. Burrows has nothing to disclose. Conflict of interest: J.F. Felix reports funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 633595 (DynaHEALTH). The Generation R Study received funding from the European Union's Horizon 2020 research and innovation programme (733206, LIFECYCLE). Conflict of interest: L.A. Salas has nothing to disclose. Conflict of interest: I. Nedeljkovic has nothing to disclose. Conflict of interest: J. Yao has nothing to disclose. Conflict of interest: S.L. Rifas-Shiman has nothing to disclose. Conflict of interest: V. Ruiz-Arenas has nothing to disclose. Conflict of interest: N. Amin has nothing to disclose. Conflict of interest: M. Bustamante has nothing to disclose. Conflict of interest: D.L. DeMeo reports grants from National Institutes of Health, and personal fees from Novartis, outside the submitted work. Conflict of interest: A.J. Henderson reports grants from Medical Research Council and Wellcome, during the conduct of the study. Conflict of interest: C.G. Howe has nothing to disclose. Conflict of interest: M-F. Hivert has nothing to disclose. Conflict of interest: M.A. Ikram has nothing to disclose. Conflict of interest: J.C. de Jongste has nothing to disclose. Conflict of interest: L. Lahousse has nothing to disclose. Conflict of interest: P.R. Mandaviya has nothing to disclose. Conflict of interest: J.B. van Meurs has nothing to disclose. Conflict of interest: M. Pinart has nothing to disclose. Conflict of interest: G.C. Sharp has nothing to disclose. Conflict of interest: L. Stolk has nothing to disclose. Conflict of interest: A.G. Uitterlinden has nothing to disclose. Conflict of interest: J.M. Antó has nothing to disclose. Conflict of interest: A.A. Litonjua has nothing to disclose. Conflict of interest: C.V. Breton has nothing to disclose. Conflict of interest: G.G. Brusselle has nothing to disclose. Conflict of interest: J. Sunyer has nothing to disclose. Conflict of interest: G.D. Smith has nothing to disclose. Conflict of interest: C.L. Relton has nothing to disclose. Conflict of interest: V.W.V. Jaddoe reports funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 633595 (DynaHEALTH). The Generation R Study received funding from the European Union's Horizon 2020 research and innovation programme (733206, LIFECYCLE). Conflict of interest: L. Duijts reports grants from Lung Foundation Netherlands and from the European Union's Horizon 2020 research and innovation programme under grant agreement number 733206 (LIFECYCLE), and speaker fees for the CIPP2016 conference from Abbvie, during the conduct of the study., (Copyright ©ERS 2019.)

Background: Infant weight gain is associated with lower lung function and a higher risk of childhood asthma. Detailed individual childhood growth patterns might be better predictors of childhood respiratory morbidity than the difference between two weight and height measurements. We assessed the associations of early childhood growth patterns with lung function and asthma at the age of 10 years and whether the child's current body mass index (BMI) influenced any association., Methods: We derived peak height and weight growth velocity, BMI at adiposity peak, and age at adiposity peak from longitudinally measured weight and height data in the first 3 years of life of 4435 children enrolled in a population-based prospective cohort study. At 10 years of age, spirometry was performed and current asthma was assessed by questionnaire. Spirometry outcomes included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC ratio, and forced expiratory flow after exhaling 75% of vital capacity (FEF 75 )., Results: Greater peak weight velocity was associated with higher FVC but lower FEV 1 /FVC and FEF 75 . Greater BMI at adiposity peak was associated with higher FVC and FEV 1 but lower FEV 1 /FVC and FEF 75 . Greater age at adiposity peak was associated with higher FVC, FEV 1 , FEV 1 /FVC and FEF 75 , particularly in children with a small size at birth, and lower odds of current asthma in boys. The child's current BMI only explained the associations of peak weight velocity and BMI at adiposity peak with FVC and FEV 1 . Peak height velocity was not consistently associated with impaired lung function or asthma., Conclusion: Peak weight velocity and BMI at adiposity peak were associated with reduced airway patency in relation to lung volume, whereas age at adiposity peak was associated with higher lung function parameters and lower risk of asthma at 10 years, particularly in boys., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Pre-eclampsia is associated with an increased risk of bronchopulmonary dysplasia, wheezing and asthma in later childhood. Currently, there are no studies available investigating maternal blood pressure measurements during multiple time-points in pregnancy and respiratory outcome measures in the child.We examined the associations of maternal blood pressure and hypertensive disorders with the risk of lower lung function, wheezing and asthma in children aged 10 years. This study among 4894 children was embedded in a population-based prospective cohort study. We used multivariate analyses, taking lifestyle and socioeconomic factors into account.We observed consistent associations per 5 mmHg higher maternal blood pressure in early pregnancy with a lower forced expiratory volume in 1 s/forced vital capacity ratio (z-score -0.03 (95% CI -0.05- -0.01)) and per 5 mmHg higher blood pressure in late pregnancy with a higher risk for current wheezing and current asthma (OR 1.07 (95% CI 1.02-1.12) and 1.06 (95% CI 1.00-1.11), respectively). We found no associations of maternal hypertensive disorders during pregnancy with child lung function, current wheezing or current asthma.Our results suggest that higher blood pressure in pregnant women is associated with lower lung function and increased risks of current wheezing and current asthma in children. The associations may be trimester specific., Competing Interests: Conflict of interest: F.A. Wilmink has nothing to disclose. Conflict of interest: H.T. den Dekker has nothing to disclose. Conflict of interest: J.C. de Jongste has nothing to disclose. Conflict of interest: I.K.M. Reiss has nothing to disclose. Conflict of interest: V.W.V. Jaddoe has nothing to disclose. Conflict of interest: E.A. Steegers has nothing to disclose. Conflict of interest: L. Duijts reports grants from the European Union's Horizon 2020 co-funded programme ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL), and from the European Union's Horizon 2020 research and innovation programme, during the conduct of the study., (Copyright ©ERS 2018.)

Genetic variants associated with adult lung function could already exert the effects on childhood lung function. We aimed to examine the associations of adult lung function-related genetic variants with childhood lung function and asthma, and whether these associations were modified by atopic predisposition, tobacco smoke exposure, or early growth characteristics. In a population-based prospective cohort study among 3347 children, we selected 7 and 20 single nucleotide polymorphisms (SNPs) associated with adult forced expiratory volume in 1 second (FEV 1 ) and FEV 1 /forced vital capacity (FEV 1 /FVC), respectively. Weighted genetic risk scores (GRSs) for FEV 1 and FEV 1 /FVC were constructed. At age 10, FEV 1 , FVC, FEV 1 /FVC, forced expiratory flow between 25% and 75% (FEF 25-75 ), and forced expiratory flow at 75% (FEF 75 ) of FVC were measured, and information on asthma was obtained by parental-reported questionnaires. The FEV 1 -GRS was associated with lower childhood FEV 1 , FEV 1 /FVC, and FEF 75 (Z-score (95% CI): -0.03 (-0.05, -0.01), -0.03 (-0.05, -0.01), and -0.04 (-0.05, -0.01), respectively, per additional risk allele). The FEV 1 /FVC-GRS was associated with lower childhood FEV 1 /FVC and FEF 75 (Z-score (95% CI): -0.04 (-0.05, -0.03) and -0.03 (-0.05, -0.02), respectively, per additional risk allele). Effect estimates of FEV 1 -GRS with FEF 25-75 , FEV 1 , FEF 75 , and FVC, and of FEV 1 /FVC-GRS with FEV 1 /FVC and FEF 25-75 were stronger among children exposed to non-atopic mothers, smoking during pregnancy or in childhood, or those born with a lower birthweight, respectively (P-values for interaction < .05). Genetic risk scores were not associated with asthma. Adult lung function-related genetic variants were associated with childhood lung function. Maternal atopy, smoking during pregnancy or in childhood, and birthweight modified the observed effects., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries 1,2 . To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

Background: Folic acid supplement use during pregnancy might affect childhood respiratory health, potentially mediated by methylenetetrahydrofolate reductase polymorphism C677T (MTHFR-C677T) carriership., Objectives: We examined the associations of maternal folic acid supplement use and folate, vitamin B 12 and homocysteine concentrations during pregnancy with childhood lung function and asthma., Methods: This study was embedded in a population-based prospective cohort study among 5653 children. Folic acid supplement use was assessed by questionnaires. Folate, vitamin B 12 and homocysteine plasma concentrations were measured in early pregnancy and at birth. At age 10 years, forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC, forced expiratory flow between 25% and 75% (FEF 25-75 ), at 75% of FVC (FEF 75 ), and asthma were examined., Results: Maternal folic acid supplement use during pregnancy was associated with higher childhood FEV 1 and FVC and with a lower FEV 1 /FVC, compared with no folic acid supplement use. Among mothers carrying MTHFR-C677T variants, preconceptional start of folic acid supplement use was associated with lower FEV 1 /FVC (-0.17 [-0.32, -0.02]) and FEF 25-75 (-0.24 [-0.40, -0.07]). Among children carrying MTHFR-C677T wild-type, a higher vitamin B 12 level at birth was associated with a lower FEV 1 (-0.07 [-0.12, -0.01]) and FVC (-0.09 [-0.15, -0.04]). Folate and homocysteine concentrations were not consistently associated with lower childhood lung function or asthma., Conclusions: Preconceptional start of maternal folic acid supplement use and higher vitamin B 12 concentrations at birth might adversely affect childhood lung function depending on MTHFR-C677T carriership. The clinical implications need to be evaluated., (© 2017 John Wiley & Sons Ltd.)

Objective: To examine the associations of maternal hemoglobin and hematocrit levels during pregnancy with childhood lung function and asthma, and whether adverse pregnancy outcomes and atopic predisposition modify the associations., Methods: In a population-based prospective cohort study among 3672 subjects, we measured maternal hemoglobin and hematocrit levels in early pregnancy, and lung function by spirometry and current asthma by questionnaire at age 10 years., Results: Higher maternal hematocrit levels, both continuously and categorized into clinical cut-offs, were associated with lower forced expiratory flow at 75% of forced vital capacity (FEF 75 ) in children (Z-score (95%CI): -0.04 (-0.07, -0.01), per increase of 1 SDS in hematocrit level; Z-score (95%CI) difference: -0.11 (-0.20, -0.03) compared with normal hematocrit levels, respectively), taking lifestyle and socio-economic factors into account. Adverse pregnancy outcomes and atopic predisposition did not modify the results. No associations of maternal hemoglobin and hematocrit with current asthma were observed., Conclusion: Higher maternal hematocrit levels during pregnancy are associated with lower childhood lung function but not with risk of asthma. Adverse pregnancy outcomes and atopic predisposition do not modify these associations. Underlying mechanisms need to be further studied., (© 2017 Wiley Periodicals, Inc.)

Background: Early-life respiratory tract infections could affect airway obstruction and increase asthma risk in later life. However, results from previous studies are inconsistent., Objective: We examined the associations of early-life respiratory tract infections with lung function and asthma in school-aged children., Methods: This study among 5197 children born between April 2002 and January 2006 was embedded in a population-based prospective cohort study. Information on physician-attended upper and lower respiratory tract infections until age 6 years (categorised into ≤ 3 and >3-6 years) was obtained by annual questionnaires. Spirometry measures and physician-diagnosed asthma were assessed at age 10 years., Results: Upper respiratory tract infections were not associated with adverse respiratory outcomes. Compared with children without lower respiratory tract infections ≤3 years, children with lower respiratory tract infections ≤3 years had a lower FEV 1 , FVC, FEV 1 :FVC and forced expiratory flow at 75% of FVC (FEF 75 ) (Z-score (95% CI): ranging from -0.22 (-0.31 to -0.12) to -0.12 (-0.21 to -0.03)) and an increased risk of asthma (OR (95% CI): 1.79 (1.19 to 2.59)). Children with lower respiratory tract infections >3-6 years had an increased risk of asthma (3.53 (2.37 to 5.17)) only. Results were not mediated by antibiotic or paracetamol use and not modified by inhalant allergic sensitisation. Cross-lagged modelling showed that results were not bidirectional and independent of preschool wheezing patterns., Conclusion: Early-life lower respiratory tract infections ≤3 years are most consistently associated with lower lung function and increased risk of asthma in school-aged children., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Rationale: Children with lower birth weight are at increased risk of asthma symptoms., Objectives: To examine associations of fetal and infant growth with childhood lung function and asthma., Methods: This study was embedded in a population-based prospective cohort study of 5,635 children. Growth was estimated by repeated ultrasounds in the second and third trimesters, and measured at birth and at 3, 6, and 12 months. At age 10 years, spirometry was performed and asthma was assessed by parental questionnaire. Restricted and accelerated growth were defined as the growth percentile change between time periods less than -0.67 and more than 0.67 SD scores (SDSs), respectively. We applied multiple regression analyses, including conditional regression analyses, to account for correlations between repeated growth measures., Measurements and Main Results: Overall greater weight in the second and third trimesters, at birth, and at 12 months was associated with higher FEV 1 and FVC (range of z-score difference, 0.04-0.08, per SDS increase in weight). Greater weight at 3 months was associated with lower FEV 1 /FVC and forced expiratory flow at 75% of the pulmonary volume (FEF 75 % ) (z-score differences [95% confidence interval]: -0.09 [-0.14 to -0.05] and -0.09 [-0.13 to -0.05] per SDS increase in weight, respectively). Restricted fetal weight growth was associated with lower childhood lung-function measures, partly depending on infant weight growth patterns (range of z-score difference, -0.25 to -0.13). Accelerated fetal weight growth was associated with higher FVC and lower FEV 1 /FVC only if followed by accelerated infant weight growth. Fetal and infant weight growth was not associated with childhood asthma., Conclusions: Both restricted fetal weight growth, partly depending on infant weight growth, and accelerated fetal and infant weight growth predispose children to lower lung function and a potential risk for respiratory diseases later in life.

Background: Breastfeeding may have immune modulatory effects that influence the development of childhood allergic sensitization and atopic diseases. We aimed to examine the associations of breastfeeding with childhood allergic sensitization, inhalant or food allergy and eczema, and whether any association was affected by disease-related modification of the exposure or modified by maternal history of allergy, eczema, or asthma., Methods: This study among 5828 children was performed in a population-based prospective cohort from fetal life onwards. We collected information on duration (<2 months, 2-4 months, 4-6 months, and ≥6 months) and exclusiveness (nonexclusive vs exclusive for 4 months) of breastfeeding in infancy by postal questionnaires. At age 10 years, inhalant allergic sensitization and food-allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy by a postal questionnaire. Data on parental-reported eczema were available from birth until age 10 years., Results: We observed no association of breastfeeding with any allergic sensitization, physician-diagnosed allergy, or combination of these outcomes. Shorter breastfeeding duration was associated with an overall increased risk of eczema (P-value for trend <.05). Nonexclusively breastfed children had an overall increased risk of eczema (adjusted odds ratio [95% confidence interval]: 1.11 [1.01, 1.23]), compared with children exclusively breastfed for 4 months. Risk period-specific sensitivity analyses, additional adjustment for ointment use for eczema at age 2 months, and cross-lagged modeling showed no consistent results for disease-related modification of the exposure. Results were not modified by maternal history of allergy, eczema, or asthma (lowest P-value for interaction=.13)., Conclusion: Shorter duration or nonexclusiveness of breastfeeding is associated with a weak overall increased risk of eczema but not allergic sensitization or physician-diagnosed allergy at age 10 years., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: It has been suggested that prenatal exposure to n-3 long-chain fatty acids protects against asthma and other allergy-related diseases later in childhood. The extent to which fish intake in pregnancy protects against child asthma and rhinitis symptoms remains unclear. We aimed to assess whether fish and seafood consumption in pregnancy is associated with childhood wheeze, asthma and allergic rhinitis., Methods: We pooled individual data from 60 774 mother-child pairs participating in 18 European and US birth cohort studies. Information on wheeze, asthma and allergic rhinitis prevalence was collected using validated questionnaires. The time periods of interest were: infancy (0-2 years), preschool age (3-4 years), and school age (5-8 years). We used multivariable generalized models to assess associations of fish and seafood (other than fish) consumption during pregnancy with child respiratory outcomes in cohort-specific analyses, with subsequent random-effects meta-analyses., Results: The median fish consumption during pregnancy ranged from 0.44 times/week in The Netherlands to 4.46 times/week in Spain. Maternal fish intake during pregnancy was not associated with offspring wheeze symptoms in any age group nor with the risk of child asthma [adjusted meta-analysis relative risk (RR) per 1-time/week = 1.01, 95% confidence interval 0.97-1.05)] and allergic rhinitis at school age (RR = 1.01, 0.99-1.03). These results were consistently found in further analyses by type of fish and seafood consumption and in sensitivity analyses., Conclusion: We found no evidence supporting a protective association of fish and seafood consumption during pregnancy with offspring symptoms of wheeze, asthma and allergic rhinitis from infancy to mid childhood., (© The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Background: Bronchopulmonary dysplasia (BPD) is the most frequent serious complication in preterm infants. We aimed to describe lung structure and ventilatory function of preterm infants with severe BPD and explored the association between early postnatal growth and these outcomes., Methods: We included preterm infants born ≤32 weeks gestational age (GA) with severe BPD. Lung structure was assessed on chest CT with the PRAGMA-BPD scoring system and ventilatory function by polysomnography (PSG) at 6 months corrected age. Postnatal growth was assessed by weight measured at birth, and at 2 and 6 months corrected age., Results: We included 49 infants (median [IQR] GA of 25.7 [24.6-26.3] weeks and mean [SD] birth weight of 760 [210] g). A 95.5% of the chest CT scans showed architectural distortion of the lung, and an oxygen desaturation index (ODI) >5 was found in 74% of the infants. An increase in GA of 1 week was associated with higher total and normal lung volume (β coefficient [95% CI]: 1.86 [0.15, 3.57] and 2.03 [0.41, 3.65]), less hypoattenuation (-4.3 [-7.70, -0.90]%) and lower ODI (-36.7 [-64.2, -9.10]%). Higher weight at 6 months was independently associated with higher total and normal lung volume, and with less severe desaturations. Increased weight gain between 2 and 6 months of corrected age was associated with less severe desaturations during sleep (β coefficient [95% CI]: 2.09 [0.49, 3.70])., Conclusion: Most preterm infants with severe BPD have structural lung abnormalities and impaired ventilatory function early in life, partly explained by birth characteristics and infant growth., (© 2017 Wiley Periodicals, Inc.)

Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium., Materials & Methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire., Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed., Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.

Background: Breastfeeding reduces the risk of asthma in early childhood, but it is not clear whether its effect on respiratory morbidity is still present in later childhood., Objective: To examine the associations of any breastfeeding, breastfeeding duration, and breastfeeding exclusiveness with lung function and asthma in school-aged children and whether associations were influenced by respiratory tract infections and maternal or child's atopic status., Methods: This study of 4,464 children was embedded in a population-based prospective cohort study. Information on breastfeeding was obtained by multiple questionnaires from birth until 1 year of age. At 10 years of age, lung function was measured by spirometry, and information on asthma was obtained by questionnaire. Adjusted linear and logistic regression models were used to examine the associations., Results: Shorter duration of breastfeeding was associated with a lower forced expiratory volume in 1 second (FEV 1 ) only (z score change, -0.01; 95% confidence interval [CI], -0.02 to -0.00) per month shorter breastfeeding, but not asthma. When categorized, breastfeeding for 2 to 4 months was associated with a lower forced vital capacity (FVC) (z score change, -0.11; 95% CI, -0.20 to -0.03) compared with breastfeeding for 6 months or longer. Nonexclusive breastfeeding for 4 months was associated with a lower FVC (z score change, -0.08; 95% CI, -0.16 to -0.01) compared with exclusive breastfeeding for 4 months. Results did not materially change after additional adjustment for lower respiratory tract infections and were not modified by maternal history of asthma or atopy, child's eczema, or inhalant allergic sensitization., Conclusion: Shorter duration and nonexclusivity of breastfeeding were associated with a lower FEV 1 and FVC but not asthma at school-age., (Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Maternal psychiatric symptoms during pregnancy might affect the developing immune system and subsequent risk of childhood atopic diseases., Objective: Our aim was to examine the associations of maternal psychiatric symptoms during pregnancy with allergic sensitization, allergy and eczema in children until age 10 years., Methods: This study among 5205 children was performed in a population-based prospective cohort from foetal life onwards. We assessed maternal and paternal psychiatric symptoms (overall, depressive, anxiety) during pregnancy and at 36 months after delivery, and maternal psychiatric symptoms at 2 and 6 months after delivery using the Brief Symptom Inventory. Inhalant and food allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy or eczema by questionnaires from birth until age 10 years. We used multivariate logistic regression, multinomial logistic regression or generalized estimating equation models where appropriate., Results: We observed no association of maternal psychiatric symptoms during pregnancy with allergic sensitization. Maternal overall psychiatric, depressive and anxiety symptoms during pregnancy were associated with an increased risk of inhalant allergy only (adjusted odds ratio (95% confidence interval) 1.96 (1.44, 2.65), 1.58 (1.25, 1.98) and 1.61 (1.27, 2.03), respectively, per 1-unit increase). Maternal overall psychiatric and anxiety symptoms during pregnancy were associated with an increased risk of eczema (1.21 (1.05, 1.39) and 1.15 (1.02, 1.29), respectively, per 1-unit increase). Effect estimates did not materially change when maternal psychiatric symptoms after delivery, or paternal psychiatric symptoms during pregnancy and after delivery were taken into account., Conclusions and Clinical Relevance: Maternal psychiatric symptoms during pregnancy were associated with increased risks of childhood inhalant allergy and eczema, independent of maternal psychiatric symptoms after delivery and of paternal psychiatric symptoms., (© 2017 John Wiley & Sons Ltd.)

Background: Animal data have suggested that the transient receptor potential ankyrin-1 (TRPA1) ion channel plays a key role in promoting airway inflammation in asthma and may mediate effects of paracetamol on asthma, yet confirmatory human data are lacking. To study associations of TRPA1 gene variants with childhood asthma and total IgE concentration, and interactions between TRPA1 and prenatal paracetamol exposure on these outcomes., Methods: We analysed associations between 31 TRPA1 single nucleotide polymorphisms (SNPs) and current doctor-diagnosed asthma and total IgE concentration at 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. We sought to confirm the most significant associations with comparable outcomes in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) and Generation R birth cohorts. In ALSPAC, we explored interactions with prenatal paracetamol exposure., Results: In ALSPAC, there was strong evidence for association between six SNPs and asthma: rs959974 and rs1384001 (per-allele odds ratio for both: 1.30 (95% CI: 1.15-1.47), p = 0.00001), rs7010969 (OR 1.28 (1.13-1.46), p = 0.00004), rs3735945 (OR 1.30 (1.09-1.55), p = 0.003), rs920829 (OR 1.30 (1.09-1.54), p = 0.004) and rs4738202 (OR 1.22 (1.07-1.39), p = 0.004). In a meta-analysis across the three cohorts, the pooled effect estimates confirmed that all six SNPs were significantly associated with asthma. In ALSPAC, TRPA1 associations with asthma were not modified by prenatal paracetamol, although associations with IgE concentration were., Conclusion: This study suggests that TRPA1 may play a role in the development of childhood asthma. (249 words)., (© 2016 The Authors Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.)

Background: Obesity and asthma often coexist. We hypothesized that detailed body fat distribution measures might be more strongly associated than body mass index (BMI) with childhood asthma., Objective: We examined the associations of total body and abdominal fat measures with respiratory resistance (Rint), fractional exhaled nitric oxide (Feno), and risks of wheezing and asthma in school-aged children., Methods: In a population-based prospective cohort study among 6178 children aged 6 years, we measured BMI, fat mass index, android/gynoid ratio, and preperitoneal and subcutaneous fat mass by physical examinations, dual-energy x-ray absorptiometry, and ultrasound, respectively. We performed Rint and Feno measurements, and assessed physician-diagnosed wheezing and asthma by questionnaires., Results: A higher BMI was associated with a higher Rint (Z score [95% CI], 0.06 [0.01-0.12]) and increased risk of wheezing (odds ratio [95% CI], 1.07 [1.00-1.14], per Z score BMI increase), but not with Feno or asthma. A high fat mass index was associated with a higher Rint (Z score [95% CI], 0.40 [0.13-0.68]). A high android/gynoid fat mass ratio was associated with a lower Feno (Sym% [95% CI], -9.8 [-16.3 to -3.4]), whereas a high preperitoneal fat mass was associated with a higher Feno (Sym% [95% CI], 6.5 [0.1-12.9]). Subcutaneous fat mass was not associated with any respiratory outcome., Conclusions: Studying detailed body fat distribution measures might provide better insight into the obesity-asthma paradigm., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Prenatal exposure to air pollution is considered to be associated with adverse effects on child health. This may partly be mediated by mechanisms related to DNA methylation., Objectives: We investigated associations between exposure to air pollution, using nitrogen dioxide (NO2) as marker, and epigenome-wide cord blood DNA methylation., Methods: We meta-analyzed the associations between NO2 exposure at residential addresses during pregnancy and cord blood DNA methylation (Illumina 450K) in four European and North American studies (n = 1,508) with subsequent look-up analyses in children ages 4 (n = 733) and 8 (n = 786) years. Additionally, we applied a literature-based candidate approach for antioxidant and anti-inflammatory genes. To assess influence of exposure at the transcriptomics level, we related mRNA expression in blood cells to NO2 exposure in 4- (n = 111) and 16-year-olds (n = 239)., Results: We found epigenome-wide significant associations [false discovery rate (FDR) p < 0.05] between maternal NO2 exposure during pregnancy and DNA methylation in newborns for 3 CpG sites in mitochondria-related genes: cg12283362 (LONP1), cg24172570 (3.8 kbp upstream of HIBADH), and cg08973675 (SLC25A28). The associations with cg08973675 methylation were also significant in the older children. Further analysis of antioxidant and anti-inflammatory genes revealed differentially methylated CpGs in CAT and TPO in newborns (FDR p < 0.05). NO2 exposure at the time of biosampling in childhood had a significant impact on CAT and TPO expression., Conclusions: NO2 exposure during pregnancy was associated with differential offspring DNA methylation in mitochondria-related genes. Exposure to NO2 was also linked to differential methylation as well as expression of genes involved in antioxidant defense pathways. Citation: Gruzieva O, Xu CJ, Breton CV, Annesi-Maesano I, Antó JM, Auffray C, Ballereau S, Bellander T, Bousquet J, Bustamante M, Charles MA, de Kluizenaar Y, den Dekker HT, Duijts L, Felix JF, Gehring U, Guxens M, Jaddoe VV, Jankipersadsing SA, Merid SK, Kere J, Kumar A, Lemonnier N, Lepeule J, Nystad W, Page CM, Panasevich S, Postma D, Slama R, Sunyer J, Söderhäll C, Yao J, London SJ, Pershagen G, Koppelman GH, Melén E. 2017. Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure. Environ Health Perspect 125:104-110; http://dx.doi.org/10.1289/EHP36., Competing Interests: The authors declare they have no actual or potential competing financial interests.

Background: Greater infant weight gain is associated with lower lung function and increased risk of childhood asthma. The role of early childhood peak growth patterns is unclear. We assessed the associations of individually derived early childhood peak growth patterns with respiratory resistance, fractional exhaled nitric oxide, wheezing patterns, and asthma until school-age., Methods: We performed a population-based prospective cohort study among 5364 children. Repeated growth measurements between 0 and 3 years of age were used to derive standard deviation scores (s.d.s) of peak height and weight velocities (PHV and PWV, respectively), and body mass index (BMI) and age at adiposity peak. Respiratory resistance and fractional exhaled nitric oxide were measured at 6 years of age. Wheezing patterns and asthma were prospectively assessed by annual questionnaires. We also assessed whether any association was explained by childhood weight status., Results: Greater PHV was associated with lower respiratory resistance [Z-score (95% CI): -0.03 (-0.04, -0.01) per s.d.s increase] (n = 3382). Greater PWV and BMI at adiposity peak were associated with increased risks of early wheezing [relative risk ratio (95% CI): 1.11 (1.06, 1.16), 1.26 (1.11, 1.43), respectively] and persistent wheezing [relative risk ratio (95% CI): 1.09 (1.03, 1.16), 1.37 (1.17, 1.60), respectively] (n = 3189 and n = 3005, respectively). Childhood weight status partly explained these associations. No other associations were observed., Conclusions: PWV and BMI at adiposity peak are critical for lung developmental and risk of school-age wheezing. Follow-up studies at older ages are needed to elucidate whether these effects persist at later ages., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The prevalence of childhood eczema varies considerably between ethnic groups. However, data from longitudinal studies remain scarce., Methods: We examined the associations of ethnic origin with the development of eczema from birth until the age of 4 years, and whether known environmental and genetic risk factors explain these associations. This study was performed in a multiethnic population-based prospective cohort among 5,082 children. Ethnic origin was based on the parents' country of birth. Data on physician-diagnosed eczema were obtained by annual questionnaires. Information on environmental risk factors was mostly obtained by questionnaires. Filaggrin (FLG) mutations (2282del4, R2447X, R501X, and S3247X) were genotyped for 3,096 children. We used generalized estimating equation models to examine the associations of ethnic origin with the longitudinal odds of eczema at 6 months and 1, 2, 3, and 4 years of age overall and independently., Results: Compared with Dutch children, Cape Verdean, Dutch Antillean, Surinamese-Creole, and Surinamese-Hindustani children had overall increased risks of eczema (OR (95%-CI): 1.53 (1.15, 2.03), 1.60 (1.21, 2.12), 1.95 (1.56, 2.44), and 2.06 (1.65, 2.57), respectively). Effect estimates for the associations of Cape Verdean and Dutch Antillean origin with eczema became non-significant after adjustment for genetic risk factors or both environmental and genetic risk factors, respectively. Surinamese-Creole and Surinamese-Hindustani children remained to have increased risks of eczema., Conclusions: Cape Verdean, Dutch Antillean, Surinamese-Creole, and Surinamese-Hindustani children had increased risks of eczema in the first 4 years of life. Environmental and genetic risk factors partly weakened these associations., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Breastfeeding is associated with a lower risk of asthma symptoms in early childhood, but its effect at older ages remains unclear. We examined the associations of duration and exclusiveness of breastfeeding with asthma outcomes in children aged 6 years, and whether these associations were explained by atopic or infectious mechanisms., Methods: We performed a population-based prospective cohort study among 5675 children. Information about breastfeeding was collected by questionnaires. At age 6 years, we measured interrupter resistance (Rint) and fractional exhaled nitric oxide (FeNO). Information about wheezing patterns (early (≤3 years only), late (>3 years only), persistent (≤3 and >3 years)), and current asthma at 6 years was derived from repeated questionnaires., Results: Compared to children who were ever breastfed, those who were never breastfed had lower FeNO levels (sympercent (95% CI): -16.0 (-24.5, -7.5)) and increased risks of late and persistent wheezing (OR(95% CI): 1.69 (1.06, 2.69) and 1.44 (1.00, 2.07), respectively). Shorter duration of breastfeeding was associated with early wheezing and current asthma (1.40 (1.14, 1.73) and 2.19 (1.29, 3.71), respectively). Less exclusive breastfeeding was associated with early wheezing (1.28 (1.08, 1.53)). Breastfeeding duration and exclusiveness were not associated with FeNO or Rint. The associations were not explained by inhalant allergies, partly by lower respiratory tract infections in early life, and to a lesser extent by lower respiratory tract infections in later life., Conclusions: Breastfeeding patterns may influence wheezing and asthma in childhood, which seems to be partly explained by infectious mechanisms., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Exposure to low levels of vitamin D in fetal life might affect the developing immune system, and subsequently the risk of childhood eczema. We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with the risk of eczema until the age of 4 years., Methods: In a population-based prospective cohort study of 3019 mothers and their children, maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels (severely deficient <25.0 nmol/l, deficient 25.0-49.9 nmol/l, sufficient 50.0-74.9 nmol/l, optimal ≥75.0 nmol/l). Eczema was prospectively assessed by annual questionnaires until the age of 4 years. Eczema patterns included never, early (age ≤1 year only), late (age >1 year only), and persistent eczema (age ≤ and >1 year). Data were assessed using the generalized estimating equations and multinomial regression models., Results: Compared with the optimal 25-hydroxyvitamin D group, sufficient, deficient, and severely deficient groups of 25-hydroxyvitamin D level in mid-gestation were not associated with the risk of overall eczema (odds ratios [95% confidence interval]: 1.09 [0.82, 1.43], 1.04 [0.87, 1.25], and 0.94 [0.81, 1.10], p-values for trend >0.05), nor with eczema per year or eczema patterns in children up to the age of 4 years. Similarly, we observed no associations of 25-hydroxyvitamin D groups at birth with any eczema outcome., Conclusion: Our results suggest that levels of 25-hydroxyvitamin D in mid-gestation and at birth are not associated with the risk of overall eczema, eczema per year, or eczema patterns among children until the age of 4 years., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma., Objective: We sought to assess the hypothesis that these associations are explained by reduced airway patency., Methods: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma., Results: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma., Conclusions: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Maternal fatty acid status during pregnancy might influence foetal immunological development and subsequently the risk of childhood atopic diseases., Objective: To examine the associations of maternal fatty acid levels during pregnancy with airway resistance and inflammation, asthma and eczema, in school-age children., Methods: This study among 4976 subjects was embedded in a population-based prospective cohort study. We measured maternal plasma glycerophospholipid fatty acid levels by gas chromatography during the second trimester of pregnancy (mean gestational age: 20.7 (± 1.1) weeks). At the age of 6 years, airway resistance and inflammation were measured by interrupter technique (Rint) and fractional exhaled nitric oxide (FeNO), and current physician-diagnosed asthma and eczema were assessed by ISAAC-based questionnaires. Multiple linear and logistic regression models were adjusted for socio-demographic, lifestyle and anthropometric factors., Results: We did not observe consistent associations of maternal total polyunsaturated fatty acid (PUFA), total n-6 PUFA, total n-3 PUFA levels and n-6/n-3 PUFA ratio during pregnancy with child's Rint and FeNO. Higher maternal total PUFA and total n-6 PUFA levels were associated with a decreased risk of childhood asthma (odds ratios (95% confidence interval): 0.76 (0.60, 0.97) and 0.71 (0.52, 0.96) per standard deviation score (SDS) increase of total PUFA and total n-6 PUFA levels, respectively) and with an increased risk of childhood eczema (1.16 (1.05, 1.28) and 1.21 (1.07, 1.37)). The observed associations were partly explained by Linoleic acid (LA, C18:2n-6) levels. Maternal total n-3 PUFA levels and n-6/n-3 PUFA ratio were not associated with current asthma and eczema. The observed associations were not explained by child's PUFA intake., Conclusions and Clinical Relevance: Higher maternal total PUFA and total n-6 PUFA levels during pregnancy seem to influence the risk of atopic diseases in childhood. The underlying mechanisms need to be further explored., (© 2015 John Wiley & Sons Ltd.)

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.

Background: Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma., Objective: We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with higher airway resistance and inflammation, and increased risks of wheezing and asthma in school-age children., Methods: We performed a population-based prospective cohort study among 3130 mothers and their children. Maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels. At age of 6, airway resistance (Rint) was measured by interrupter technique and airway inflammation by fractional exhaled nitric oxide (FENO) using NIOX chemiluminescence analyser. Wheezing and asthma were prospectively assessed by annual questionnaires until age 6., Results: Maternal levels of 25-hydroxyvitamin D in mid-gestation were not associated with Rint, FeNO, wheezing patterns, or asthma. Children in the lowest tertile of 25-hydroxyvitamin D levels at birth had a higher Rint (Z-score (95% confidence interval [95% CI]): -0.42 (-0.84, -0.01), P-value for trend< 0.05), compared to those in the highest tertile group. The effect estimate attenuated when child's current 25-hydroxyvitamin D level was taken into account [Z-score (95% CI): -0.55 (-1.08, 0.01)]., Conclusion and Clinical Relevance: Low levels of 25-hydroxyvitamin D at birth were associated with a higher airway resistance in childhood. Additional adjustment for child's current 25-hydroxyvitamin D level reduced the effect size of the association. Further studies are needed to replicate these findings and to examine mechanisms underlying the observed association and the long-term consequences., (© 2015 John Wiley & Sons Ltd.)

Background: Antenatal hydronephrosis (ANH) is characteristic for congenital obstructive abnormalities of the urinary tract (COAUT). COAUT is the most common cause of urinary tract infections (UTI's) in newborns. The prognosis of mild to moderate ANH is unclear. The aim of this study was to determine the diagnostic value of antenatal ultrasound screening for ANH in order to inform patients correctly., Methods: A retrospective cohort study over the period 2009-2011, evaluating all structural ultrasounds and proven cases of ANH. Also, evaluation of all patients diagnosed with UTIs caused by COAUT in the same period., Results: About 7003 children underwent antenatal screening. Of them, 0.7% (n = 47) were diagnosed with ANH. In the same period, 257 children without ANH had a proven UTI. Of them, 4.3% (n = 11) were diagnosed with COAUT, which was not found during antenatal screening. The predictive value of the antenatal ultrasound was higher in the third trimester than the second trimester (sensitivity 0.97 versus 0.62, respectively)., Conclusion: Antenatal ultrasound screening is a reliable method in diagnosing ANH. Third trimester scanning is more specific for diagnosing ANH than second trimester scanning. Our findings allow collaborating gynecologists and pediatricians to inform patients more accurately in the future after the antenatal detection of COAUT.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Background: Tobacco smoke exposure has been associated with early childhood asthma symptoms. We assessed the associations of tobacco smoke exposure during pregnancy and childhood with wheezing patterns, asthma, airway interrupter resistance (Rint), and fractional exhaled nitric oxide (Feno) in school-age children and whether birth characteristics explained the associations., Methods: This study was embedded in a population-based prospective cohort study among 6,007 children. Paternal and maternal smoking during pregnancy (never, first trimester only, continued), secondhand tobacco smoke exposure during childhood, wheezing patterns, and asthma were prospectively assessed by questionnaires. Wheezing patterns were defined as never, early (≤ 3 years only), late (> 3 years only), and persistent (≤ 3 and > 3 years) wheezing. Rint and Feno were measured at age 6 years. Birth characteristics were available from registries., Results: Continued maternal smoking during pregnancy was associated with increased risks of early and persistent wheezing (OR: 1.24 [1.01, 1.52]; 1.48 [1.13, 1.95]) and asthma (1.65 [1.07, 2.55], for at least five cigarettes per day), but not with Rint or Feno. Birth characteristics did not explain these associations. Childhood tobacco smoke exposure was associated with higher Rint (difference z score: 0.45 [0.00, 0.90]), but this effect attenuated after adjustment for birth characteristics. Maternal smoking during first trimester only or paternal smoking during pregnancy was not associated with Rint, Feno, wheezing, or asthma., Conclusions: Continued maternal smoking during pregnancy was associated with increased risks of asthma outcomes in school-age children, whereas childhood tobacco smoke exposure was associated with higher Rint. Birth characteristics may explain part of these associations.

Background: Previous studies suggest that caesarean section may influence the risk of childhood asthma. We examined the associations of different modes of delivery with childhood wheezing patterns, asthma, fractional exhaled nitric oxide (FeNO) and airway interrupter resistance (Rint) up to school age., Methods: This study among 6,128 children was embedded in a population-based prospective cohort study. Information on mode of delivery was obtained from midwives and hospital registries. Wheezing patterns from birth onwards and ever physician-diagnosed asthma at age 6 yr were assessed by questionnaires. FeNO and Rint were measured at age 6 yr. We used multivariate polynomial, logistic and linear regression models., Results: Compared with vaginal delivery, caesarean section was associated with increased risks of early and persistent wheezing up to school age [odds ratios (95% confidence interval): 1.36 (1.06, 1.75) and 1.73 (1.24, 2.40), respectively]. The effect sizes of elective and emergency caesarean section with wheezing outcomes were similar. Only elective caesarean section was associated with a higher FeNO level [sympercent (95% CI): 12.7 (0.6, 24.8)]. We did not observe associations of mode of delivery with asthma or Rint. Also, vacuum- or forceps-assisted vaginal delivery was not associated with any asthma or related outcome., Conclusions: Both elective and emergency caesarean sections are associated with increased risks of early and persistent wheezing up to school age. This might be explained by increased airway inflammation reflected by higher FeNO levels., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.