Network medicine-based epistasis detection in complex diseases: ready for quantum computing.

Most heritable diseases are polygenic. To comprehend the underlying genetic architecture, it is crucial to discover the clinically relevant epistatic interactions (EIs) between genomic single nucleotide polymorphisms (SNPs) (1-3). Existing statistical computational methods for EI detection are mostly limited to pairs of SNPs due to the combinatorial explosion of higher-order EIs. With NeEDL (network-based epistasis detection via local search), we leverage network medicine to inform the selection of EIs that are an order of magnitude more statistically significant compared to existing tools and consist, on average, of five SNPs. We further show that this computationally demanding task can be substantially accelerated once quantum computing hardware becomes available. We apply NeEDL to eight different diseases and discover genes (affected by EIs of SNPs) that are partly known to affect the disease, additionally, these results are reproducible across independent cohorts. EIs for these eight diseases can be interactively explored in the Epistasis Disease Atlas (https://epistasis-disease-atlas.com). In summary, NeEDL demonstrates the potential of seamlessly integrated quantum computing techniques to accelerate biomedical research. Our network medicine approach detects higher-order EIs with unprecedented statistical and biological evidence, yielding unique insights into polygenic diseases and providing a basis for the development of improved risk scores and combination therapies.

Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study.

RATIONALE: Early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. OBJECTIVES: To assess the accuracy of gas chromatography-mass spectrometry based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. METHODS: This study encompassed a discovery (SysPharmPediA) and validation phase (U-BIOPRED, PANDA). Firstly, exhaled VOCs that discriminated asthma control levels were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled, based on asthma control test scores and number of severe attacks in the past year. Additionally, potential of VOCs in predicting two or more future severe asthma attacks in SysPharmPediA was evaluated. MEASUREMENTS AND MAIN RESULTS: Complete data were available for 196 children (SysPharmPediA=100, U-BIOPRED=49, PANDA=47). In SysPharmPediA, after randomly splitting the population into training (n=51) and test sets (n=49), three compounds (acetophenone, ethylbenzene, and styrene) distinguished between uncontrolled and controlled asthmatics. The area under the receiver operating characteristic curve (AUROCC) for training and test sets were respectively: 0.83 (95% CI: 0.65-1.00) and 0.77 (95% CI: 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ±0.06 (UBIOPRED) and 0.68 ±0.05 (PANDA). Attacks prediction tests, resulted in AUROCCs of 0.71 (95% CI 0.51-0.91) and 0.71 (95% CI 0.52-0.90) for training and test sets. CONCLUSIONS: Exhaled metabolites analysis might enable asthma control classification in children. This should stimulate further development of exhaled metabolites-based point-of-care tests in asthma.

Urinary eicosanoid levels in early life and risk of atopic disease in childhood.

BACKGROUND: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.

Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma.

BACKGROUND: Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT). OBJECTIVE: To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT. METHODS: MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort. RESULTS: An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p=0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p=0.006) for subjects with a higher number of elevated T2 biomarkers. CONCLUSIONS: HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype. TRIAL REGISTRATION NUMBER: NCT01433523.

Urban metabolic and airway immune profiles increase the risk of infections in early childhood.

BACKGROUND: Infections in childhood remain a leading global cause of child mortality and environmental exposures seem crucial. We investigated whether urbanicity at birth was associated with the risk of infections and explored underlying mechanisms. METHODS: Children (n=633) from the COPSAC2010 mother-child cohort were monitored daily with symptom diaries of infection episodes during the first 3 years and prospectively diagnosed with asthma until age 6 years. Rural and urban environments were based on the CORINE land cover database. Child airway immune profile was measured at age 4 weeks. Maternal and child metabolomics profiling were assessed at pregnancy week 24 and at birth, respectively. RESULTS: We observed a mean (SD) total number of infections of 16.3 (8.4) consisting mainly of upper respiratory infections until age 3 years. Urban versus rural living increased infection risk (17.1 (8.7) vs 15.2 (7.9), adjusted incidence rate ratio; 1.15 (1.05-1.26), p=0.002) and altered the child airway immune profile, which increased infection risk (principal component 1 (PC1): 1.03 (1.00-1.06), p=0.038 and PC2: 1.04 (1.01-1.07), p=0.022). Urban living also altered the maternal and child metabolomic profiles, which also increased infection risk. The association between urbanicity and infection risk was partly mediated through the maternal metabolomic and child airway immune profiles. Finally, urbanicity increased the risk of asthma by age 6 years, which was mediated through early infection load (pACME<0.001). CONCLUSION: This study suggests urbanicity as an independent risk factor for early infections partly explained by changes in the early metabolic and immunological development with implications for later risk of asthma.

Bacterial colonisation of the airway in neonates and risk of asthma and allergy until age 18†years.

BACKGROUND: We previously showed an association between neonatal bacterial airway colonisation and increased risk of persistent wheeze/asthma until age 5 years. Here, we study the association with persistent wheeze/asthma and allergy-related traits until age 18 years. METHODS: We investigated the association between airway colonisation with Streptococcus pneumoniae, Moraxella catarrhalis and/or Haemophilus influenzae in 1-month-old neonates from the COPSAC2000 mother-child cohort and the development of persistent wheeze/asthma and allergy-related traits longitudinally until age 18 years using generalised estimating equations. Replication was sought in the similarly designed COPSAC2010 cohort of 700 children. RESULTS: Neonatal airway colonisation was present in 66 (21%) out of 319 children and was associated with a 4-fold increased risk of persistent wheeze/asthma (adjusted OR 4.01 (95% CI 1.76-9.12); p<0.001) until age 7 years, but not from age 7 to 18 years. Replication in the COPSAC2010 cohort showed similar results using 16S data. Colonisation was associated with an increased number of exacerbations (adjusted incidence rate ratio 3.20 (95% CI 1.38-7.44); p<0.01) until age 7 years, but not from age 7 to 18 years. Colonisation was associated with increased levels of blood eosinophils (adjusted geometric mean ratio 1.24 (95% CI 1.06-1.44); p<0.01) and tumour necrosis factor (TNF)-α (adjusted geometric mean ratio 1.09 (95% CI 1.02-1.16); p=0.01) until age 12 years. There were no associations with lung function, bronchial reactivity, fractional exhaled nitric oxide, allergic sensitisation, total IgE or atopic dermatitis up to age 18 years. CONCLUSIONS: Neonatal airway colonisation was associated with early-onset persistent wheeze/asthma, exacerbations, elevated blood eosinophils and elevated TNF-α in blood, most prominent in early childhood, thereafter diminishing and no longer evident by age 18 years.

Genetic predisposition to high BMI increases risk of early life respiratory infections and episodes of severe wheeze and asthma.

BACKGROUND: High BMI is an established risk factor for asthma, but the underlying mechanisms remain unclear.Objective: To increase understanding of the BMI-asthma relationship by studying the association between genetic predisposition to higher body mass index (BMI) and asthma, infections, and other asthma-traits during childhood. METHODS: Data was obtained from the two ongoing COPSAC mother-child cohorts. Polygenic risk score (PRS) for adult BMI were calculated for each child. Replication was done in the large-scale iPSYCH cohort using data on hospitalization for asthma and infections. RESULTS: In the COPSAC cohorts (n=974), the adult BMI PRS was significantly associated with lower respiratory tract infections (LRTI) (IRR 1.20 95% CI 1.08-1.33, FDR=0.005) age 0-3 years and episodes of severe wheeze (IRR 1.30, 1.06-1.60, FDR=0.04) age 0-6 years. LRTI partly mediated the association between the adult BMI PRS and severe wheeze (proportion mediated: 0.59, 0.28-2.24, pACME 2E-16). In contrast, these associations were not mediated through the child's current BMI and the PRS was not associated with an asthma diagnosis or reduced lung function up to age 18. The associations were replicated in iPSYCH (n=114 283), where the adult BMI PRS significantly increased the risk of hospitalizations for LRTI and wheeze or asthma during childhood to age 18 years. CONCLUSION: Children with genetic predisposition to higher BMI had increased risk of LRTI and severe wheeze, independent of the child's current BMI. These results shed further light on the complex relationship between BMI and asthma.

European Respiratory Society Statement on preschool wheezing disorders: updated definitions, knowledge gaps, and proposed future research directions.

Since the publication of the European Respiratory Society (ERS) Task Force reports on the management of preschool wheezing in 2008 and 2014, a large body of evidence has accumulated suggesting the clinical phenotypes that were proposed, episodic (viral) wheezing and multiple-trigger wheezing, do not relate to underlying airway pathology and may not help determine response to treatment. Specifically, using clinical phenotypes alone may no longer be appropriate, and new approaches that can be used to inform clinical care are needed for future research. This ERS Task Force reviewed the literature published after 2008 related to preschool wheezing and has suggested the criteria used to define wheezing disorders in preschool children should include age of diagnosis (0 to <6 years), confirmation of wheezing on at least one occasion, and more than one episode of wheezing ever.Furthermore, diagnosis and management may be improved by identifying treatable traits, including inflammatory biomarkers (blood eosinophils, aeroallergen sensitisation) associated with type-2 immunity and differential response to inhaled corticosteroids, lung function parameters, and airway infection. However, more comprehensive use of biomarkers/treatable traits in predicting the response to treatment requires prospective validation. There is evidence that specific genetic traits may help guide management, but these must be adequately tested. In addition, the Task Force identified an absence of caregiver-reported outcomes, caregiver/self-management options, and features that should prompt specialist referral for this age group. Priorities for future research include a focus on identifying i) mechanisms driving preschool wheezing, ii) biomarkers of treatable traits and efficacy of interventions in those without allergic sensitisation/eosinophilia, iii) the need to include both objective outcomes and caregiver-reported outcomes in clinical trials, iv) the need for a suitable action plan for children with preschool wheezing and v) a definition of severe/difficult-to-treat preschool wheezing.

Infantile colic is associated with development of later constipation and atopic disorders.

BACKGROUND: Infantile colic is a common condition with limited knowledge about later clinical manifestations. We evaluated the role of the early life gut microbiome in infantile colic and later development of atopic and gastrointestinal disorders. METHODS: Copenhagen Prospective Studies on Asthma in Childhood2010 cohort was followed with 6 years of extensive clinical phenotyping. The 1-month gut microbiome was analyzed by 16S rRNA sequencing. Infantile colic was evaluated at age 3 months by interviews. Clinical endpoints included constipation to age 3 years and prospectively diagnosed asthma and atopic dermatitis in the first 6 years of life, and allergic sensitization from skin prick tests, specific Immunoglobulin E, and component analyses. RESULTS: Of 695 children, 55 children (7.9%) had infantile colic. Several factors were associated with colic including race, breastfeeding, and pets. The 1-month gut microbiome composition and taxa abundances were not associated with colic, however a sparse Partial Least Squares model including combined abundances of nine species was moderately predictive of colic: median, cross-validated AUC = 0.627, p = .003. Children with infantile colic had an increased risk of developing constipation (aOR, 2.88 [1.51-5.35], p = .001) later in life, but also asthma (aHR, 1.69 [1.02-2.79], p = .040), atopic dermatitis (aHR, 1.84 [1.20-2.81], p = .005) and had a higher number of positive allergic components (adjusted difference, 116% [14%-280%], p = .012) in the first 6 years. These associations were not mediated by gut microbiome differences. CONCLUSIONS: We link infantile colic with risk of developing constipation and atopic disorders in the first 6 years of life, which was not mediated through an altered gut microbiome at age 1-month. These results suggest infantile colic to involve gastrointestinal and/or atopic mechanisms.

Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10.

INTRODUCTION: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC2010 mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10. METHODS: The COPSAC2010 cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS). RESULTS: A total of 604 (86 %) of the 700 children in the COPSAC2010 cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores. DISCUSSION: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.

Preventive effects of prenatal administration of OM-85/BV on asthma and respiratory infection risk in the offspring: A review of animal models.

Asthma is the most common chronic disease in childhood affecting the daily lives of many patients despite current treatment regimens. Therefore, the need for new therapeutic approaches is evident, where a primary prevention strategy is the ultimate goal. Studies of children born to mothers in farming environments have shown a lower risk of respiratory infections and asthma development. Already at birth, these newborns have demonstrated accelerated maturation and upregulation of host defense immune functions suggesting a prenatal transplacental training of the innate immune system through maternal microbial exposure. This mechanism could possibly be utilized to help prevent both respiratory infections and asthma in young children. Human studies exploring the potential preventative effects of pregnancy bacterial lysate treatment on asthma and respiratory infections are lacking, however, this has been studied in experimental studies using mice through administrations of the bacterial lysate OM-85. This review will present the current literature on the immunomodulatory effects relevant for respiratory infections and asthma in the offspring of mice treated with OM-85 throughout pregnancy. Further, the review will discuss the cellular and molecular mechanisms behind these effects. In conclusion, we found promising results of an accelerated immune competence and improved resistance to airway challenges as a result of prenatal bacterial lysate treatment that may pave the way for implementing this in human trials to prevent asthma and respiratory infections.

A systematic review and meta-analysis on absolute eosinophil counts and the risk of asthma in preschool children with wheezing: An EAACI Task Force Report.

Preschool children with wheezing disorders pose diagnostic and therapeutic challenges and consume substantial healthcare resources. Peripheral eosinophil blood count (EBC) has been proposed as a potential indicator for future asthma development. This review by the European Academy of Allergy and Clinical Immunology (EAACI) Preschool Wheeze Task Force aimed to provide systematic evidence for the association between increased EBC and the risk of future asthma, as well as to identify potential cutoff values. In February 2023, a search of PubMed, EMBASE, and Cochrane Library databases was conducted to identify studies comparing EBCs in preschool children with wheezing who continued to wheeze later in life and those who did not. Included observational studies focused on children aged <6 years with a wheezing disorder, assessment of their EBCs, and subsequent asthma status. No language or publication date restrictions were applied. Among the initial 3394 studies screened, 10 were included in the final analysis, involving 1225 patients. The data from these studies demonstrated that high EBC in preschool children with wheezing is associated with future asthma development, with odds ratios of 1.90 (95% CI: 0.45-7.98, p = .38), 2.87 (95% CI: 1.38-5.95, p < .05), and 3.38 (95% CI: 1.72-6.64, p < .05) for cutoff values in the <300, 300-449, and ≥450 cells/µL ranges, respectively. Defining a specific cutoff point for an elevated EBC lacks consistency, but children with EBC >300 cells/µL are at increased risk of asthma. However, further research is needed due to the limitations of the included studies. Future investigations are necessary to fully elucidate the discussed association.

Characteristics of Adults With Severe Asthma in Childhood: A 60-Year Follow-up Study.

BACKGROUND: Childhood asthma is a prevalent condition with potential impact on adult life. RESEARCH QUESTION: In a 60-year follow-up study of adults with a history of severe childhood asthma, what are the potential differences in characteristics between individuals with persistent asthma and asthma remission in adulthood? STUDY DESIGN AND METHODS: Danish adults with a history of childhood asthma and a 4-month stay in at an asthma care facility in Kongsberg, Norway (1950-1979) in childhood were included. Recruitment was carried out through social media and personal invitation letters. Participants completed questionnaires and underwent spirometry, bronchial provocation, and bronchodilator reversibility and blood tests. Asthma remission was defined as no use of asthma medication and no asthma symptoms within the past 12 months, with the remaining participants being classified as having current asthma. RESULTS: Among 1,394 eligible participants, 232 participants completed the follow-up. Ninety percent had current asthma, of whom 26% reported exacerbations in the past year. Only 16% of all the participants were managed in secondary care. Common comorbidities were allergic rhinitis (60%), hypertension (21%), eczema (16%), and cataract (8%). Compared with participants in remission, participants with persistent asthma showed higher total IgE (P = .03) and both lower FEV1 % predicted (P = .03) and FEV1 to FVC ratio (P < .001), as well as numerically higher fractional exhaled nitric oxide and blood eosinophil count. INTERPRETATION: Our 60-year follow-up study of adults with a history of severe childhood asthma revealed that nine of 10 participants still had current asthma. Persistent asthma was associated with lower lung function and higher levels of type 2 inflammatory biomarkers compared with asthma remission.

Fish oil supplementation during pregnancy, anthropometrics, and metabolic health at age ten: A randomized clinical trial.

BACKGROUND: We previously reported that children of mothers who received fish oil supplementation during pregnancy had higher body mass index [BMI (in kg/m2)] at 6 y of age as well as a concomitant increase in fat-, muscle, and bone mass, but no difference in fat percentage. OBJECTIVES: Here, we report follow-up at age 10 y including assessment of metabolic health. METHODS: This is a follow-up analysis of a randomized clinical trial conducted among 736 pregnant females and their offspring participating in the Copenhagen Prospective Studies on Asthma in Childhood mother-child cohort. The intervention was 2.4 g n-3 (ω-3) Long-Chain PolyUnsaturated Fatty Acid (n-3 LCPUFA) or control daily from pregnancy week 24 until 1 wk after birth. Outcomes were anthropometric measurements, body composition from Bioelectrical Impedance Analysis, blood pressure, concentrations of triglycerides, cholesterol, glucose, and C-peptide from fasting blood samples, and a metabolic syndrome score was calculated. Anthropometric measurements and body composition were prespecified secondary endpoints of the n-3 LCPUFA trial, and others were exploratory. RESULTS: Children in the n-3 LCPUFA group had a higher mean BMI at age 10 year compared to the control group: 17.4 (SD: 2.44) compared with 16.9 (2.28); P = 0.020 and a higher odds ratio of having overweight (odds ratio: 1.53; 95% CI: 1.01, 2.33; P = 0.047). This corresponded to differences in body composition in terms of increased lean mass (0.49 kg; 95% CI: -0.20, 1.14; P = 0.17), fat mass (0.49 kg; 95% CI: -0.03, 1.01; P = 0.06), and fat percent (0.74%; 95% CI: -0.01, 1.49; P = 0.053) compared to the control group. Children in the n-3 LCPUFA group had a higher metabolic syndrome score compared to the control (mean difference: 0.19; 95% CI: -0.02, 0.39; P = 0.053). CONCLUSIONS: In this randomized clinical trial, children of mothers receiving n-3 LCPUFA supplementation had increased BMI at age 10 y, increased risk of being overweight, and a tendency of increased fat percentage and higher metabolic syndrome score. These findings suggest potential adverse health effects from n-3 LCPUFA supplementation during pregnancy and need to be replicated in future independent studies. This trial was registered at clinicaltrials.gov as NCT00798226.

Maternal Diet Associates with Offspring Bone Mineralization, Fracture Risk and Enamel Defects in Childhood and Influences the Prenatal Effect of High-Dose Vitamin D Supplementation.

We previously demonstrated a beneficial effect of high-dose vitamin D in pregnancy on offspring bone and dental health. Here, we investigated the effect of maternal dietary patterns during pregnancy on the risk of bone fractures, bone mineralization and enamel defects until age 6 years in the offspring. Further, the influence of diet on the effect of high-dose vitamin D was analyzed in the COPSAC2010 mother-child cohort including 623 mother-child pairs. A weighted network analysis on FFQs revealed three specific maternal dietary patterns that associated (Bonferroni p < 0.05) with both offspring bone and dental health. The effect of prenatal high-dose (2800 IU/day) vs. standard-dose (400 IU/day) vitamin D on offspring bone mineral content (adjusted mean difference (aMD): 33.29 g, 95% CI: 14.48-52.09, p < 0.001), bone mineral density (aMD: 0.02 g/cm2 (0.01-0.04), p < 0.001), fracture risk (adjusted incidence rate ratio: 0.36 (0.16-0.84), p = 0.02), and enamel defects in primary (adjusted odds ratio (aOR): 0.13 (0.03-0.58), p < 0.01) and permanent molars (aOR: 0.25; (0.10-0.63), p < 0.01) was most pronounced when mothers had lower intake of fruit, vegetables, meat, eggs, sweets, whole grain, offal and fish. This study suggests that prenatal dietary patterns influence offspring bone and dental development, and should be considered in order to obtain the full benefits of vitamin D to enhance personalized supplementation strategy.

Burden and Subtypes of Early Life Infections Increase the Risk of Asthma.

BACKGROUND: Early life respiratory tract infections have been linked to the development of asthma, but studies on the burden and subtypes of common infections in asthma development are sparse. OBJECTIVE: To examine the association between burden of early life infections, including subtypes, with the risk of asthma from age 3 to 10 years and lung function at age 10 years. METHODS: We included 662 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort, for whom infections such as colds, acute tonsillitis, acute otitis media, pneumonia, gastroenteritis, and fever were registered prospectively in daily diaries at age 0 to 3 years and asthma was diagnosed longitudinally from age 3 to 10 years. The association between the burden of infection and subtypes and risk of asthma was analyzed by generalized estimating equations. RESULTS: The children experienced a median of 16 infections (interquartile range, 12-23 infections) at age 0 to 3 years. Children with a high burden of infections (above the median) had an increased risk of asthma at age 3 to 10 years (adjusted odds ratio = 3.61; 95% CI, 2.39-5.45; P < .001), which was driven by colds, pneumonia, gastroenteritis, and fever episodes (P < .05) but not by acute otitis media and tonsillitis. Lower lung function measures at age 10 years were associated with the burden of pneumonia but not the overall infection burden. The association between colds and the risk of asthma was significantly higher in children with allergic rhinitis at age 6 years (P interaction = .032). CONCLUSION: A high burden of early life infections in terms of colds, pneumonia, gastroenteritis, and fever is associated with an increased risk of developing asthma, particularly in children with respiratory allergy. Strategies to diminish these early life infections may offer a path for the primary prevention of childhood asthma.

Bilirubin metabolism in early life and respiratory health during preschool age: A combined analysis of two independent birth cohorts.

BACKGROUND: Bilirubin has antioxidant properties, and elevated levels within the normal range have been associated with improved lung function and decreased risk of asthma in adults, but studies of young children are scarce. Here, we investigate associations between bilirubin in early life and respiratory health endpoints during preschool age in two independent birth cohorts. METHODS: Bilirubin metabolites were assessed at ages 0.5, 1.5, and 6 years in COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and ages 1, 3, and 6 years in the VDAART (The Vitamin D Antenatal Asthma Reduction Trial) cohort. Meta-analyses were done to summarize the relationship between levels of bilirubin metabolites and asthma, infections, lung function, and allergic sensitization until age 6 across the cohorts. Interaction with the glucuronosyltransferase family 1 member A1 (UGT1A) genotype encoding for an enzyme in the bilirubin metabolism was explored, and metabolomics data were integrated to study underlying mechanisms. FINDINGS: Increasing bilirubin (Z,Z) at ages 1.5-3 years was associated with an increased risk of allergic sensitization (adjusted relative risk [aRR] = 1.85 [1.20-2.85], p = 0.005), and age 6 bilirubin (Z,Z) also showed a trend of association with allergic sensitization at age 6 (aRR = 1.31 [0.97-1.77], p = 0.08), which showed significant interaction for the age 6 bilirubin (Z,Z)xUGT1A genotype. Further, increasing bilirubin (E,E), bilirubin (Z,Z), and biliverdin at ages 1.5-3 years was associated with a lower forced expiratory volume at age 6 (aRR range = 0.81-0.91, p < 0.049) but without a significant interaction with the UGT1A genotype (p interactions > 0.05). Network analysis showed a significant correlation between bilirubin metabolism and acyl carnitines. There were no associations between bilirubin metabolites and the risk of asthma and infections. CONCLUSIONS: Bilirubin metabolism in early life may play a role in childhood respiratory health, particularly in children with specific UGT1A genotypes. FUNDING: The Lundbeck Foundation (Grant no R16-A1694), The Ministry of Health (Grant no 903516), Danish Council for Strategic Research (Grant no 0603-00280B), and The Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The Vitamin D Antenatal Asthma Reduction Trial (VDDART, ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from NHLBI, U54TR001012 from the National Centers for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL123915 and R01HL141826. S.T.W. was supported by R01HL091528 from the NHLBI, UG3OD023268 from Office of The Director, National Institute of Health, and P01HL132825 from the NHLBI.

The infant gut virome is associated with preschool asthma risk independently of bacteria.

Bacteriophage (also known as phage) communities that inhabit the gut have a major effect on the structure and functioning of bacterial populations, but their roles and association with health and disease in early life remain unknown. Here, we analyze the gut virome of 647 children aged 1 year from the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort, all deeply phenotyped from birth and with longitudinally assessed asthma diagnoses. Specific temperate gut phage taxa were found to be associated with later development of asthma. In particular, the joint abundances of 19 caudoviral families were found to significantly contribute to this association. Combining the asthma-associated virome and bacteriome signatures had additive effects on asthma risk, implying an independent virome-asthma association. Moreover, the virome-associated asthma risk was modulated by the host TLR9 rs187084 gene variant, suggesting a direct interaction between phages and the host immune system. Further studies will elucidate whether phages, alongside bacteria and host genetics, can be used as preclinical biomarkers for asthma.