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Background: Atopic diseases, obesity and neuropsychiatric disorders are lifestyle-related and environmental-related chronic inflammatory disorders, and the incidences have increased in the last years., Objective: To outline the design of the 18-year follow-up of the Copenhagen Prospective Study on Asthma in Childhood (COPSAC 2000 ) birth cohort, where risk factors of atopic diseases, obesity and neuropsychiatric disorders are identified through extensive characterisation of the environment, along with deep clinical phenotyping and biosampling for omics profiling., Methods: COPSAC 2000 is a Danish prospective clinical birth cohort study of 411 children born to mothers with asthma who were enrolled at 1 month of age and closely followed at the COPSAC clinical research unit through childhood for the development of atopic diseases. At the 18-year follow-up visit, biomaterial (hair, blood, urine, faeces, throat, and skin swabs, nasal lining fluid and scraping, and hypopharyngeal aspirates) and extensive information on environmental exposures and risk behaviours were collected along with deep metabolic characterisation and multiorgan investigations including anthropometrics, heart, lungs, kidneys, intestines, bones, muscles and skin. Neuropsychiatric diagnoses were captured from medical records and registers accompanied by electronic questionnaires on behavioural traits and psychopathology., Results: A total of 370 (90%) of the 411 cohort participants completed the 18-year visit. Of these, 25.1% had asthma, 23.4% had a body mass index >25 kg/m 2 and 16.8% had a psychiatric diagnosis in childhood. A total of 68.7% drank alcohol monthly, and when drinking, 22.2% drank >10 units. Of the participants, 31.4% were currently smoking, and of these, 24.1% smoked daily. A total of 23.8% had tried taking drugs, and 19.7% reported having done self-destructive behaviour. The mean screen time per day was 6.0 hours., Conclusion: This huge dataset on health and habits, exposures, metabolism, multiorgan assessments and biosamples from COPSAC 2000 by age 18 provides a unique opportunity to explore risk factors and underlying mechanisms of atopic disease and other lifestyle-related, non-communicable diseases such as obesity and neuropsychiatric disorders, which are highly prevalent in the community and our cohort., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Vitamin D deficiency and elevated high sensitivity C-reactive protein (hs-CRP) have been associated with several health outcomes, but knowledge on early life trajectories and association between 25 hydroxyvitamin D (25(OH)D) and hs-CRP is lacking. We investigated the association between longitudinal measurements of 25(OH)D and hs-CRP, respectively, from pregnancy to childhood and throughout childhood in two Danish mother-child cohorts-the COPSAC 2010 and COPSAC 2000 . In COPSAC 2010 , there was an association between 25(OH)D concentrations at week 24 in pregnancy and at age 6 months in childhood ( n = 633): estimate (95% CI); 0.114 (0.041;0.187), p = 0.002, and between 25(OH)D at age 6 months and 6 years ( n = 475): 0.155 (0.083;0.228), p < 0.001. This was also demonstrated in the COPSAC 2000 cohort between 25(OH)D concentrations in cord blood and at age 4 years ( n = 188): 0.294 (0.127;0.461), p < 0.001 and at age 6 months and 4 years ( n = 264): 0.260 (0.133;0.388), p < 0.001. In COPSAC 2000 , we also found an association between hs-CRP at age 6 months and 12 years in childhood ( n = 232): 0.183 (0.076;0.289), p < 0.001. Finally, we found a negative association between the cross-sectional measurements of 25(OH)D and hs-CRP at age 6 months ( n = 613) in COPSAC 2010 : -0.004 (-0.008;-0.0004), p = 0.030, but this was not replicated in COPSAC 2000 . In this study, we found evidence of associations across timepoints of 25(OH)D concentrations from mid-pregnancy to infancy and through childhood and associations between hs-CRP levels during childhood, although with weak correlations. We also found a negative cross-sectional association between 25(OH)D and hs-CRP concentrations in COPSAC 2010 proposing a role of vitamin D in systemic low-grade inflammation, though this association was not present in COPSAC 2000 .

Early exposure to environmental triggers may elicit trajectories to chronic inflammatory disease through deregulated immune responses. To address relations between early immune competence and development of childhood asthma, we performed functional immune profiling of 186 parameters in blood of 541 18-month-old infants and examined links between their response phenotype and development of transient or persistent disease at 6 years of age. An abnormal neutrophil-linked antiviral response was associated with increased risk of transient asthma. Children who exhibited persistent asthma at year 6 showed enhanced interleukin-5 (IL-5) and IL-13 production in stimulated T cells at 18 months of age, which was associated with early life bacterial colonization of the airways. These findings highlight the early appearance of distinct immune characteristics in infants developing different asthma endotypes during childhood., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations., Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis., Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included., Main Outcomes and Measures: Type 2 diabetes and glycemic traits., Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration., Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

High sensitivity C-reactive protein (hs-CRP) is a marker of systemic low-grade inflammation and associated with chronic inflammatory diseases. It is unknown whether maternal and infant hs-CRP levels are correlated and little is known about risk factors in early childhood. Hs-CRP were measured in mothers during pregnancy week 24 (N = 690), and one-week postpartum (N = 675) and in their children age 6 mo (N = 640) enrolled in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010 ) cohort. The risk factor analysis included anthropometrics, environmental exposures and CRP-Genetic Risk Score (GRS). Mother's body mass index (BMI), use of antibiotics, smoking, cesarean delivery and season were associated with higher maternal hs-CRP level, whereas higher social circumstances were associated with lower hs-CRP level (p < 0.05). Child's BMI, siblings, bacterial airway colonization, current infection, CRP-genetic risk score and season were associated with higher hs-CRP at age 6 mo (all p < 0.05). Mother's hs-CRP level in pregnancy week 24 was associated with hs-CRP level in the child at 6 mo: β-coefficient = 0.11 [95% CI: 0.01-0.20], R 2  = 0.22, p = 0.03. The association was unchanged adjusted for all significant risk factors. Systemic low-grade inflammation in pregnant mothers and their offspring is correlated independently of BMI, environmental exposures and genetic risk factors.

The originally published version of this Article contained an incorrect version of Figure 3 that was introduced following peer review and inadvertently not corrected during the production process. Both versions contain the same set of abundance data, but the incorrect version has the children's asthma status erroneously disconnected from the abundance data, thereby producing the non-representative p values and graphic presentations. These errors have now been rectified, with the correct version of Figure 3 replaced in both the PDF and HTML versions of the Article.

The composition of the human gut microbiome matures within the first years of life. It has been hypothesized that microbial compositions in this period can cause immune dysregulations and potentially cause asthma. Here we show, by associating gut microbial composition from 16S rRNA gene amplicon sequencing during the first year of life with subsequent risk of asthma in 690 participants, that 1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 years. This association is only apparent among children born to asthmatic mothers, suggesting that lacking microbial stimulation during the first year of life can trigger their inherited asthma risk. Conversely, adequate maturation of the gut microbiome in this period may protect these pre-disposed children.

Background: Systemic low-grade inflammation has been demonstrated in a range of the frequent noncommunicable diseases (NCDs) proposing a shared mechanism, but is largely unexplored in relation to allergic sensitization. We therefore aimed to investigate the possible association with childhood allergic sensitization., Methods: High-sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and chemokine (C-X-C motif) ligand 8 (CXCL8) were measured in plasma at age 6 months (N = 214) and 7 years (N = 277) in children from the Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC 2000 ) birth cohort. Allergic sensitization against common inhalant and food allergens was determined longitudinally at ages ½, 1½, 4 and 6 years by specific IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principal component analyses (PCAs)., Results: Adjusted for gender, recent infections, and a CRP genetic risk score, hs-CRP at 7 years was associated with concurrent elevated specific IgE against any allergen [adjusted OR (aOR) = 1.40; 95% CI, 1.14-1.72; P = 0.001], aeroallergens (aOR, 1.43; 1.15-1.77; P = 0.001), food allergens (aOR, 1.31; 95% CI, 1.02-1.67; P = 0.04), sensitization without any clinical allergy symptoms (aOR = 1.40; 1.06-1.85; P = 0.02), and with similar findings for skin prick tests. The other inflammatory markers were not univariately associated with sensitization, but multiparametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6 months were not associated with subsequent development of sensitization phenotypes., Conclusions: Elevated hs-CRP is associated with allergic sensitization in school-aged children suggesting systemic low-grade inflammation as a phenotypic characteristic of this early-onset NCD., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring., Methods: We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010 ) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization., Results: A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization., Conclusions: Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)