Search

Background: The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE‐mediated food allergy are unknown. Objective: To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multiethnic cohorts and responses to OIT. Methods: Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N = 384), a Costa Rican cohort of children with asthma (N = 1040), and a peanut OIT trial (N = 20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterward). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Results: Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q = 2.4 × 10−20) and linoleic acid derivatives (q = 3.8 × 10−5) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q = 4.1 × 10−8), eicosanoids (q = 7.9 × 10−7), and histidine pathways (q =.015). In particular, the bile acid lithocholate (4.97 [1.93, 16.14], p =.0027), the eicosanoid leukotriene B4 (3.21 [1.38, 8.38], p =.01), and the histidine metabolite urocanic acid (22.13 [3.98, 194.67], p =.0015) were higher in SU. Conclusions: We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T‐cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorders are rapidly increasing in prevalence and have been linked to various environmental risk factors. Mounting evidence suggests a potential role of vitamin D in child neurodevelopment, though the causal mechanisms remain largely unknown. Here, we investigate how vitamin D deficiency affects children's communication development, particularly in relation to Autism Spectrum Disorder (ASD). We do so by developing an integrative network approach that combines metabolomic profiles, clinical traits, and neurodevelopmental data from a pediatric cohort. Our results show that low levels of vitamin D are associated with changes in the metabolic networks of tryptophan, linoleic, and fatty acid metabolism. These changes correlate with distinct ASD-related phenotypes, including delayed communication skills and respiratory dysfunctions. Additionally, our analysis suggests the kynurenine and serotonin sub-pathways may mediate the effect of vitamin D on early life communication development. Altogether, our findings provide metabolome-wide insights into the potential of vitamin D as a therapeutic option for ASD and other communication disorders. [ABSTRACT FROM AUTHOR]

Background: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. Method s : We performed targeted LC–MS/MS‐based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta‐analyzed together. Results: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p‐value range: 1.863E‐04 to 2.24E‐3], increased ceramide levels were associated with asthma risk factors [meta p‐value range: 7.75E‐5 to.013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. Conclusion: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations. [ABSTRACT FROM AUTHOR]

Rationale: The role and timing of vitamin D supplementation in the prevention of asthma has not been fully elucidated. Objective: To describe the association between prenatal and postnatal vitamin D with offspring asthma outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial. Methods: We classified 748 mother--offspring pairs into four groups based on the mother's randomization to receive high-dose versus low-dose (4,400 IU vs. 400 IU) vitamin D supplementation during pregnancy and the offspring parent-reported high-dose versus low-dose (>400 IU vs.,400 IU) vitamin D supplementation as estimated by intake of vitamin D drops or infant formula. We used logistic regression to test the association of the four vitamin D exposure groups--"mother-low/infant-low (reference)," "mother-high/infant-high," "mother-high/infant-low," and "mother-low/infant-high"--with offspring asthma and/or recurrent wheeze at age 3 years, active asthma at age 6 years, and atopic asthma at age 6 years. Results: The risk of asthma and/or recurrent wheeze at 3 years was lowest in the mother-high/infant-low group (adjusted odds ratio vs. mother-low/infant-low, 0.39; 95% confidence interval, 0.16--0.88, P = 0.03). When stratifying by history of exclusive breastfeeding until age 4 months, the protective effect in the mother-high/infant-low group was seen only among exclusively breastfed infants (odds ratio vs. mother-low/infant-low, 0.19; 95% confidence interval, 0.04--0.68; P = 0.02). We did not observe any significant associations with active or atopic asthma at age 6 years. Conclusions: We observe that high-dose prenatal and low-dose postnatal vitamin D supplementation may be associated with reduced offspring asthma or recurrent wheeze by age 3 years, but this association may be confounded by the protective effect of breastfeeding. [ABSTRACT FROM AUTHOR]

Introduction: Meta-analyses across diverse independent studies provide improved confidence in results. However, within the context of metabolomic epidemiology, meta-analysis investigations are complicated by differences in study design, data acquisition, and other factors that may impact reproducibility. Objective: The objective of this study was to identify maternal blood metabolites during pregnancy (> 24 gestational weeks) related to offspring body mass index (BMI) at age two years through a meta-analysis framework. Methods: We used adjusted linear regression summary statistics from three cohorts (total N = 1012 mother–child pairs) participating in the NIH Environmental influences on Child Health Outcomes (ECHO) Program. We applied a random-effects meta-analysis framework to regression results and adjusted by false discovery rate (FDR) using the Benjamini–Hochberg procedure. Results: Only 20 metabolites were detected in all three cohorts, with an additional 127 metabolites detected in two of three cohorts. Of these 147, 6 maternal metabolites were nominally associated (P < 0.05) with offspring BMI z-scores at age 2 years in a meta-analytic framework including at least two studies: arabinose (Coefmeta = 0.40 [95% CI 0.10,0.70], Pmeta = 9.7 × 10–3), guanidinoacetate (Coefmeta = − 0.28 [− 0.54, − 0.02], Pmeta = 0.033), 3-ureidopropionate (Coefmeta = 0.22 [0.017,0.41], Pmeta = 0.033), 1-methylhistidine (Coefmeta = − 0.18 [− 0.33, − 0.04], Pmeta = 0.011), serine (Coefmeta = − 0.18 [− 0.36, − 0.01], Pmeta = 0.034), and lysine (Coefmeta = − 0.16 [− 0.32, − 0.01], Pmeta = 0.044). No associations were robust to multiple testing correction. Conclusions: Despite including three cohorts with large sample sizes (N > 100), we failed to identify significant metabolite associations after FDR correction. Our investigation demonstrates difficulties in applying epidemiological meta-analysis to clinical metabolomics, emphasizes challenges to reproducibility, and highlights the need for standardized best practices in metabolomic epidemiology. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case‐control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (≤30 ng/mL) during gestation from 10 to 18 weeks, using differential expression analysis. Methods: Using quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10–18 weeks of gestation in the same VDAART cohort to identify differentially expressed (DE) miRNAs associated with preeclampsia and vitamin D status. For the validation of the expression of circulating miRNA signatures in the placenta, the HTR‐8/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA‐target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein‐protein interaction (PPI) network and hub targets were determined. As experimental validation, we examined the gene and protein expression of IGF1R, one of the key hub genes, as a target of the DE miRNA, miR‐182‐5p, in response to a miR‐182‐5p mimic in HTR‐8/SVneo cells. Results: Pregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9/16 = 56% upregulated, FDR <.05). Thirteen miRNAs (13/16 = 81.3%) were detected in HTR‐8/SVneo cells. Overall, 16 DE miRNAs had 122 targets, of which 87 were unique. Network analysis demonstrated that the 32 targets of DE miRNA signatures created a connected subnetwork in the preeclampsia module with CXCL8, CXCL10, CD274, MMP9 and IGF1R having the highest connectivity and centrality degree. In an in vitro validation experiment, the introduction of an hsa‐miR‐182‐5p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR‐8/SVneo cells. Conclusions: The integration of the circulating DE miRNA and mRNA signatures associated preeclampsia added additional insights into the subclinical molecular signature of preeclampsia. Our systems and network biology approach revealed several biological pathways, including IGF‐1, that may play a role in the early pathophysiology of preeclampsia. These pathways and signatures also denote potential biomarkers for the early stages of preeclampsia and suggest possible preventive measures. [ABSTRACT FROM AUTHOR]

Problem: Promotion of a healthy pregnancy is dependent on a coordinated immune response that minimizes inflammation at the maternal–fetal interface. Few studies investigated the effect of fetal sex on proinflammatory biomarkers during pregnancy and whether maternal race could impact this association. We aimed to examine whether fetal sex could, independently of maternal race/ethnicity and the condition of pregnancy (normal vs. complicated), impact inflammatory markers (C‐reactive protein [CRP] and interleukin‐8 [IL‐8] levels) in early and late pregnancy. Methods of study: This study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART, N = 816). Maternal serum CRP and IL‐8 levels were measured in early and late pregnancy (10–18 and 32–38 weeks of gestation, respectively). Five hundred and twenty‐eight out of 816 pregnant women who participated in the trial had available CRP and IL‐8 measurements at both study time points. We examined the association of fetal sex with early and late CRP and IL‐8 levels and their paired sample difference. We further investigated whether maternal race/ethnicity, pregnancy complications (i.e., preeclampsia and gestational diabetes), and early pregnancy body mass index (BMI) could affect the association between these two biomarkers and fetal sex adjusting for potential confounders. For this purpose, we used generalized linear and logistic regression models on log‐normalized early and late CRP and IL‐8 levels as well as their split at median to form high and low groups. Results: Women pregnant with male fetuses (266/528 = 56.5%) had higher CRP levels in early to mid‐pregnancy (β =.18: 95% confidence interval [CI]: CI = 0.03–0.32; p =.02). Twenty‐seven percent (143/528) of the study subjects were Hispanic. Hispanic African American [AA] women and women of races other than White and AA had higher levels of CRP at early to mid‐pregnancy compared with White women (β =.57; 95% CI: 0.17–0.97; p <.01 and β =.27; 95% CI: 0.05–0.48; p =.02, respectively). IL‐8 levels were not associated with fetal sex in early and late pregnancy (p's >.05). Other factors such as gestational diabetes and early pregnancy BMI were associated with higher CRP levels and higher CRP and IL‐8 levels, respectively. Dichotomizing log‐normalized cytokine levels at the median in a sensitivity analysis, women with male fetuses had lower odds of high (above‐median) IL‐8 levels at early pregnancy. Also, women with races other than AA and White carrying male fetuses had higher odds of having high (above‐median) late‐pregnancy CRP and early‐pregnancy IL‐8 levels (adjusted odds ratio [aOR] = 3.80, 95% CI: 0.24–1.23; p =.02 and aOR = 3.57; 95% CI: 0.23–1.03; p =.02, respectively). Of the pregnancy complications, women with gestational diabetes mellitus had a higher paired difference of early and late pregnancy CRP levels (β =.38; 95% CI: 0.09–0.68; p =.01), but no difference in IL‐8 levels (p's >.05). No associations between the inflammatory markers and preeclampsia were found. Conclusion: Fetal sex is associated with CRP in early pregnancy and an association with IL‐8 in early pregnancy is implied. Our study further indicates that maternal race/ethnicity could be a contributing factor in the relationship between fetal sex and inflammatory responses during pregnancy. However, the specificity and level of the contribution might vary by type of cytokine, pregnancy stage, and other confounding factors such as BMI that may impact these associations. [ABSTRACT FROM AUTHOR]

Traditional approaches to understanding metabolomics in mental illness have focused on investigating a single disorder or comparisons between diagnoses, but a growing body of evidence suggests substantial mechanistic overlap in mental disorders that could be reflected by the metabolome. In this study, we investigated associations between global plasma metabolites and abnormal scores on the depression, anxiety, and phobic anxiety subscales of the Brief Symptom Inventory (BSI) among 405 older males who participated in the Normative Aging Study (NAS). Our analysis revealed overlapping and distinct metabolites associated with each mental health dimension subscale and four metabolites belonging to xenobiotic, carbohydrate, and amino acid classes that were consistently associated across all three symptom dimension subscales. Furthermore, three of these four metabolites demonstrated a higher degree of alteration in men who reported poor scores in all three dimensions compared to men with poor scores in only one, suggesting the potential for shared underlying biology but a differing degree of perturbation when depression and anxiety symptoms co-occur. Our findings implicate pathways of interest relevant to the overlap of mental health conditions in aging veterans and could represent clinically translatable targets underlying poor mental health in this high-risk population. [ABSTRACT FROM AUTHOR]

Respiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquid-chromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10–7 to 0.002) and improved lung function metrics (P = 0.020–0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life. Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226. [ABSTRACT FROM AUTHOR]

Associations of omega-3 fatty acids (n-3) with allergic diseases are inconsistent, perhaps in part due to genetic variation. We sought to identify and validate genetic variants that modify associations of n-3 with childhood asthma or atopy in participants in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC). Dietary n-3 was derived from food frequency questionnaires and plasma n-3 was measured via untargeted mass spectrometry in early childhood and children aged 6 years old. Interactions of genotype with n-3 in association with asthma or atopy at age 6 years were sought for six candidate genes/gene regions and genome-wide. Two SNPs in the region of DPP10 (rs958457 and rs1516311) interacted with plasma n-3 at age 3 years in VDAART (p = 0.007 and 0.003, respectively) and with plasma n-3 at age 18 months in COPSAC (p = 0.01 and 0.02, respectively) in associationwith atopy. Another DPP10 region SNP, rs1367180, interacted with dietary n-3 at age 6 years in VDAART (p = 0.009) and with plasma n-3 at age 6 years in COPSAC (p = 0.004) in association with atopy. No replicated interactions were identified for asthma. The effect of n-3 on reducing childhood allergic disease may differ by individual factors, including genetic variation in the DPP10 region. [ABSTRACT FROM AUTHOR]

Shifts in the maternal gut microbiome and vitamin D deficiency during pregnancy have been associated, separately, with health problems for both the mother and the child. Yet, they have rarely been studied simultaneously. Here, we analyzed the gut microbiome (from stool samples obtained in late pregnancy) and vitamin D level (from blood samples obtained both in early and late pregnancy) data of pregnant women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized controlled trial of vitamin D supplementation during pregnancy, to investigate the association of vitamin D status on the pregnant women's microbiome. To find associations, we ran linear regressions on alpha diversity measures, PERMANOVA tests on beta diversity distances, and used the ANCOM-BC and Maaslin2 algorithms to find differentially abundant taxa. Analyses were deemed significant using a cut-off p-value of 0.05. We found that gut microbiome composition is associated with the vitamin D level in early pregnancy (baseline), the maternal gut microbiome does not show a shift in response to vitamin D supplementation during pregnancy, and that the genus Desulfovibrio is enriched in women without a substantial increase in vitamin D level between the first and the third trimesters of pregnancy. We conclude that increasing the vitamin D level during pregnancy could be protective against the growth of sulfate-reducing bacteria such as Desulfovibrio, which has been associated with chronic intestinal inflammatory disorders. More in-depth investigations are needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Background: Asthma is a heterogeneous disease with high morbidity. Advancement in high-throughput multi-omics approaches has enabled the collection of molecular assessments at different layers, providing a complementary perspective of complex diseases. Numerous computational methods have been developed for the omics-based patient classification or disease outcome prediction. Yet, a systematic benchmarking of those methods using various combinations of omics data for the prediction of asthma development is still lacking. Objective: We aimed to investigate the computational methods in disease status prediction using multi-omics data. Method: We systematically benchmarked 18 computational methods using all the 63 combinations of six omics data (GWAS, miRNA, mRNA, microbiome, metabolome, DNA methylation) collected in The Vitamin D Antenatal Asthma Reduction Trial (VDAART) cohort. We evaluated each method using standard performance metrics for each of the 63 omics combinations. Results: Our results indicate that overall Logistic Regression, Multi-Layer Perceptron, and MOGONET display superior performance, and the combination of transcriptional, genomic and microbiome data achieves the best prediction. Moreover, we find that including the clinical data can further improve the prediction performance for some but not all the omics combinations. Conclusions: Specific omics combinations can reach the optimal prediction of asthma development in children. And certain computational methods showed superior performance than other methods. [ABSTRACT FROM AUTHOR]

Background: Intestinal microenvironmental perturbations may increase food allergy risk. We hypothesize that children with clinical food allergy, those with food sensitization, and healthy children can be differentiated by intestinal metabolites in the first years of life. Methods: In this ancillary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we performed untargeted metabolomic profiling in 824 stool samples collected at ages 3–6 months, 1 year and 3 years. Subjects included 23 with clinical food allergy at age 3 and/or 6 years, 151 with food sensitization but no clinical food allergy, and 220 controls. We identified modules of correlated, functionally related metabolites and sought associations of metabolite modules and individual metabolites with food allergy/sensitization using regression models. Results: Several modules of functionally related intestinal metabolites were reduced among subjects with food allergy, including bile acids at ages 3–6 months and 1 year, amino acids at age 3–6 months, steroid hormones at 1 year, and sphingolipids at age 3 years. One module primarily containing diacylglycerols was increased in those with food allergy at age 3–6 months. Fecal caffeine metabolites at age 3–6 months, likely derived from breast milk, were increased in those with food allergy and/or sensitization (beta = 5.9, 95% CI 1.0–10.8, p =.02) and were inversely correlated with fecal bile acids and bilirubin metabolites, though maternal plasma caffeine levels were not associated with food allergy and/or sensitization. Conclusions: Several classes of bioactive fecal metabolites are associated with food allergy and/or sensitization including bile acids, steroid hormones, sphingolipids, and caffeine metabolites. [ABSTRACT FROM AUTHOR]

Rationale: Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Objectives: Evaluate associations of plasma EV-miRNAs with lung function. Methods: The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study). Measurements and Main Results: In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted P value,0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity. Conclusions: Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease. [ABSTRACT FROM AUTHOR]

Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age <12 months) enrolled in one of the 53 prospective cohort studies in the ECHO Program during 2001–2021. The exposure was bronchiolitis hospitalization during infancy. The outcome was a diagnosis of asthma by a physician by age 12 years. We examined their longitudinal association and determined the potential effect modifications of major demographic factors. Results: The analytic cohort consisted of 11,762 infants, 10% of whom had bronchiolitis hospitalization. Overall, 15% subsequently developed asthma. In the Cox proportional hazards model adjusting for 10 patient-level factors, compared with the no-bronchiolitis hospitalization group, the bronchiolitis hospitalization group had a significantly higher rate of asthma (14% vs. 24%, HR = 2.77, 95%CI = 2.24–3.43, p < 0.001). There was significant heterogeneity by race and ethnicity (Pinteraction = 0.02). The magnitude of the association was greater in non-Hispanic White (HR = 3.77, 95%CI = 2.74–5.18, p < 0.001) and non-Hispanic Black (HR = 2.39, 95%CI = 1.60–3.56; p < 0.001) infants, compared with Hispanic infants (HR = 1.51, 95%CI = 0.77–2.95, p = 0.23). Conclusions: According to the nationwide cohort data, infants hospitalized with bronchiolitis are at a higher risk for asthma, with quantitative heterogeneity in different racial and ethnic groups. [ABSTRACT FROM AUTHOR]

Maternal infection and stress during the prenatal period have been associated with adverse neurodevelopmental outcomes in offspring, suggesting that biomarkers of increased inflammation in the mothers may associate with poorer developmental outcomes. In 491 mother–child pairs from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we investigated the association between maternal levels of two inflammatory biomarkers; interleukin-8 (IL-8) and C-Reactive Protein (CRP) during early (10–18 wks) and late (32–38 wks) pregnancy with offspring scores in the five domains of the Ages and Stages Questionnaire, a validated screening tool for assessing early life development. We identified a robust association between early pregnancy IL-8 levels and decreased fine-motor (β: −0.919, 95%CI: −1.425, −0.414, p = 3.9 × 10−4) and problem-solving skills at age two (β: −1.221, 95%CI: −1.904, −0.414, p = 4.9 × 10−4). Associations between IL-8 with other domains of development and those for CRP did not survive correction for multiple testing. Similarly, while there was some evidence that the detrimental effects of early pregnancy IL-8 were strongest in boys and in those who were not breastfed, these interactions were not robust to correction for multiple testing. However, further research is required to determine if other maternal inflammatory biomarkers associate with offspring neurodevelopment and work should continue to focus on the management of factors leading to increases in IL-8 levels in pregnant women. [ABSTRACT FROM AUTHOR]

Recurrent respiratory infections are a leading cause of morbidity and mortality in early life, but there is no broadly accepted means to identify infection-prone children during this highly vulnerable period. In this study, we investigated associations between steroid metabolites and incident respiratory infections in two pre-birth cohorts to identify novel metabolomic signatures of early infection proneness. Children from the Vitamin D Antenatal Asthma Reduction Trial and the Copenhagen Prospective Studies on Asthma in Childhood were included, and profiling was performed on plasma samples collected at ages 1 and 6 years. Both cohorts recorded incidence of lower respiratory infections, upper respiratory infections, ear infections, and colds. Poisson regression analysis assessed the associations between 18 steroid metabolites and the total number of respiratory infections that occurred in offspring during follow-up. We found that steroid metabolites across androgenic, corticosteroid, pregnenolone, and progestin classes were reduced in children that suffered more infections, and these patterns persisted at age 6 years, generally reflecting consistency in direction of effect and significance. Our analysis suggested steroid metabolite measurement may be useful in screening for infection proneness during this critical developmental period. Future studies should clinically evaluate their potential utility as a clinical screening tool. [ABSTRACT FROM AUTHOR]

Rationale: The biochemical mechanisms underlying lung function are incompletely understood.Objectives: To identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery-the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk, n=10 460) and validation-the VA Normative Aging Study (NAS) metabolomic cohort (n=437).Methods: We ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and p<0.05.Measurements and Main Results: Of 156 metabolites that associated with FEV1 in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV1/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV1 and FEV1/FVC.Conclusions: The validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers. [ABSTRACT FROM AUTHOR]

Background: Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the association between 25(OH)D during fetal development and risk of childhood ADHD.Methods: Maternal plasma 25(OH)D was measured at 10-18 and 32-38 weeks of gestation, with sufficiency defined as 25(OH)D ≥ 30 ng/ml. Offspring ADHD status between ages 6-9 years was measured by parent report of clinical ADHD diagnosis among 680 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial. Association between maternal 25(OH)D and child ADHD was assessed using logistic regression, adjusting for maternal age, race and ethnicity. Effect modification by offspring sex was also assessed.Results: No associations between maternal 25(OH)D at 10-18 weeks of gestation and offspring ADHD were observed. In the third trimester, we observed associations between maternal vitamin D sufficiency and offspring ADHD [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.26-0.84], in addition to maternal 25(OH)D sufficiency category, comparing the deficient (OR 0.34, 95% CI 0.12-0.94), insufficient (OR 0.41, 95% CI 0.15-1.10) and sufficient (OR 0.20, 95% CI 0.08-0.54) categories against highly deficient 25(OH)D, respectively. Stratified analyses revealed a protective association for sufficient maternal 25(OH)D and child ADHD among males (OR 0.47, 95% CI 0.23-0.94); the synergy index for additive effect modification of risk was 1.78 (95% CI 0.62-5.08).Conclusions: Higher levels of maternal vitamin D in the third trimester are associated with lower risk of ADHD in offspring, with modest evidence for a stronger effect among male offspring. However, larger studies will be necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials (RCTs) suggest a protective effect of high‐dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs. Methods: In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) RCT, we analyzed the effect of high‐dose vitamin D during pregnancy on the risk of persistent wheeze age 0‐3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Results: In COPSAC2010, VDR SNP rs1544410 influenced the effect of high‐dose vitamin D: maternal Pinteraction =.049 and child Pinteraction =.001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10‐0.68), P =.006, and no effect among CT or CC genotypes: 0.85 (0.48‐1.51), P =.58 and 0.94 (0.47‐1.89), P =.87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC2010 or VDAART: all Pinteraction ≥.17. Conclusions: We found that the effect of high‐dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC2010 RCT, but not VDAART, which may be due to population differences. [ABSTRACT FROM AUTHOR]

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated.Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data.Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort.Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05.Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme. [ABSTRACT FROM AUTHOR]

Attrition, erosion, and abrasion result in alterations to the tooth and manifest as tooth wear. Each classification acts through a distinct process that is associated with unique clinical characteristics. Accurate prevalence data for each classification are not available since indices do not necessarily measure one specific etiology, or the study populations may be too diverse in age and characteristics. The treatment of teeth in each classification will depend on identifying the factors associated with each etiology. Some cases may require specific restorative procedures, while others will not require treatment. A review of the literature points to the interaction of the three entities in the initiation and progression of lesions that may act synchronously or sequentially, synergistically or additively, or in conjunction with other entities to mask the true nature of tooth wear, which appears to be multifactorial. [ABSTRACT FROM AUTHOR]

Attrition, erosion, and abrasion result in alterations to the tooth and manifest as tooth wear. Each classification acts through a distinct process that is associated with unique clinical characteristics. Accurate prevalence data tor each classification are not available since indices do not necessarily measure one specific ecology, or the study populations may be too diverse in age and characteristics. The treatment of teeth in each classification will depend on identifying the factors associated with each etiology. Some cases may require specific restorative procedures, while others will not require treatment. A review of the literature points to the interaction of the three entities in the initiation and progression of lesions that may act synchronously or sequentially, synergistically or additively, or in contraction with other entities to mask the true nature of tooth wear, which appears to be multifactorial (Quintessence lnt 2003;34:435-446) [ABSTRACT FROM AUTHOR]

Asthma is a clinical syndrome that affects all age groups. Asthma prevalence worldwide has seen a rapid increase in the latter part of the last century. Recent data has shown that asthma prevalence has plateaued and even decreased in some areas of the world, despite continuing to increase in other areas of the world. Many risk factors have been associated with asthma and the differences in distributions of these risk factors may explain the differences in prevalence. This article will review recent trends in the prevalence of asthma and recent studies that investigate risk factors of asthma. [ABSTRACT FROM AUTHOR]

Background: We conducted a literature review on the studies that investigated the relationship of preterm birth, including spontaneous preterm birth (sPTB), with vitamin D status. Overall, these studies demonstrated that the incidence of sPTB was associated with maternal vitamin D insufficiency in early pregnancy. However, the potential mechanisms and biological pathways are unknown. Objectives: To investigate early pregnancy gene expression signatures associated with both vitamin D insufficiency and sPTB. We further constructed a network of these gene signatures and identified the common biological pathways involved. Study design: We conducted peripheral blood transcriptome profiling at 10–18 weeks of gestation in a nested case-control cohort of 24 pregnant women who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In this cohort, 8 women had spontaneous preterm delivery (21–32 weeks of gestation) and 17 women had vitamin D insufficiency (25-hydroxyvitamin D < 30 ng/mL). We separately identified vitamin D-associated and sPTB gene signatures at 10 to 18 weeks and replicated the overlapping signatures in the mid-pregnancy peripheral blood of an independent cohort with sPTB cases. Result: At 10–18 weeks of gestation, 146 differentially expressed genes (25 upregulated) were associated with both vitamin D insufficiency and sPTB in the discovery cohort (FDR < 0.05). Of these genes, 43 (25 upregulated) were replicated in the independent cohort of sPTB cases and controls with normal pregnancies (P < 0.05). Functional enrichment and network analyses of the replicated gene signatures suggested several highly connected nodes related to inflammatory and immune responses. Conclusions: Our gene expression study and network analyses suggest that the dysregulation of immune response pathways due to early pregnancy vitamin D insufficiency may contribute to the pathobiology of sPTB. [ABSTRACT FROM AUTHOR]

The article discusses maternal asthma and preeclampsia have reported to be associated with increased asthma incidence in children of affected mothers. Topics include maternal asthma associating with increased risk for preeclampsia development; and children monitoring by phone every 3 months and in person yearly for 6 years, the children's health, respiratory symptoms, and medications have assessed.

Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva–Boston, and the Generation R Study–Rotterdam). We performed covariate-adjusted epigenome-wide association meta-analysis and employed pathway and regional analyses of results. Seven-hundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylation – time interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization. [ABSTRACT FROM AUTHOR]

Background: While familial clustering of asthma is known, few studies have reported on the relative roles of paternal and maternal asthma and the role of maternal asthma control in pregnancy on the risk for asthma in the child. Objective: We aimed to investigate the relative roles of paternal asthma, maternal asthma, and maternal asthma control during pregnancy on the risk of asthma or recurrent wheeze in 3‐year‐old children and how prenatal and cord blood vitamin D status might affect this risk. Methods: Data from 806 women, their partners (biologic fathers of the infants), and their children participated in the Vitamin D Antenatal Asthma Reduction Trail (VDAART, clinicaltrials.gov identification number NCT00920621) were used for this cohort analysis. The parental report of physician‐diagnosed asthma or recurrent wheeze in offspring was the main outcome. Weibull regression models for interval‐censored event times were used to estimate the main variables of interests and additional covariates on the outcome. Results: The highest risk was observed among children with both parents being asthmatic relative to non‐asthmatic parents (aHR = 2.30, 95% CI: 1.35‐3.84), and less so if only the mother was asthmatic (aHR = 1.70, 95% CI: 1.17‐2.40). In the subset of children born to asthmatic mothers, the risk for asthma was higher in those who were born to mothers whose asthma was uncontrolled (aHR = 1.60, 95% CI: 1.02‐2.54). Children whose mothers had sufficient vitamin D status (25Hydroxyvitamin D ≥ 30 ng/mL) at early and late pregnancy and had cord blood vitamin D sufficiency demonstrated a lower risk of asthma/recurrent wheeze than children who had insufficient cord blood vitamin D status at birth (aHR = 0.47, 95% CI: 0.27‐0.83). Conclusion and Clinical Relevance: Careful attention to maternal asthma control, monitoring vitamin D status, and correcting insufficiency at early pregnancy and maintaining the sufficiency status throughout pregnancy have potential preventive roles in offspring asthma or recurrent wheeze. [ABSTRACT FROM AUTHOR]

Rationale: Maternal asthma and preeclampsia have independently been reported to be associated with increased asthma incidence in children of affected mothers. Maternal asthma is also associated with increased risk of preeclampsia development. However, the joint effect of these maternal conditions on child asthma risk is unknown.Objectives: To study whether development of preeclampsia among pregnant women with asthma was associated with higher risk of childhood asthma in the VDAART (Vitamin D Antenatal Asthma Reduction Trial).Methods: A total of 806 pregnant women and their offspring at high risk of asthma or atopy, who were followed from VDAART enrollment (10-18 wk of gestation) through the child's third birthday, were included in this cohort analysis. Preeclampsia status was determined by chart review, obstetrician diagnosis, and adjudication by a panel of obstetricians. Child asthma was the main outcome as determined by parental report of a physician diagnosis, and the risk of child asthma was also examined if accompanied by recurrent wheeze. The main risk variable of interest was a four-level ordered variable defined for each mother, with values without asthma without preeclampsia, without asthma with preeclampsia, with asthma without preeclampsia, and with asthma with preeclampsia during their pregnancy. We examined the trend of outcome proportions across these categories. To account for differences in maternal and child characteristics, we used a Weibull regression model for interval-censored data to compare the incidence of child asthma by age of 3 years across the maternal variable categories.Measurements and Main Results: The incidence of asthma in 3-year-old children was 9.90% (44/445), 17.95% (7/39), 22.11% (65/294), and 32.14% (9/28) among those born to mothers without asthma and without preeclampsia, mothers without asthma with preeclampsia, mothers with asthma without preeclampsia, and mothers with asthma with preeclampsia, respectively. The incidences demonstrated an increasing trend in risk of child asthma across the maternal groups (P for trend <0.001). After accounting for potential confounders and using time to report of childhood asthma as analysis outcome, risk of asthma was greater among children born to mothers with asthma without preeclampsia, compared with mothers without asthma without preeclampsia (adjusted hazard ratio, 2.18; 95% confidence interval, 1.46-3.26). This risk was 50% greater for children born to mothers with asthma who developed preeclampsia during pregnancy (adjusted hazard ratio, 2.68; 95% confidence interval, 1.30-5.61). The trend in asthma and recurrent wheeze proportions across the maternal groups' children also indicated a higher risk for children born to mothers with asthma with preeclampsia (adjusted hazard ratio, 4.73; 95% confidence interval, 2.20-10.07; P for trend <0.001).Conclusions: Preeclampsia is associated with increased risk of early life childhood asthma in children less than 3 years old over and above that associated with maternal asthma alone. The results implicate the interplay between maternal factors as strong predictors of offspring asthma and in utero maternal-fetal immune perturbations and developmental dysregulations associated with preeclampsia. [ABSTRACT FROM AUTHOR]

To explore novel methods for the analysis of metabolomics data, we compared the ability of Partial Least Squares Discriminant Analysis (PLS-DA) and Bayesian networks (BN) to build predictive plasma metabolite models of age three asthma status in 411 three year olds (n = 59 cases and 352 controls) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART) study. The standard PLS-DA approach had impressive accuracy for the prediction of age three asthma with an Area Under the Curve Convex Hull (AUCCH) of 81%. However, a permutation test indicated the possibility of overfitting. In contrast, a predictive Bayesian network including 42 metabolites had a significantly higher AUCCH of 92.1% (p for difference < 0.001), with no evidence that this accuracy was due to overfitting. Both models provided biologically informative insights into asthma; in particular, a role for dysregulated arginine metabolism and several exogenous metabolites that deserve further investigation as potential causative agents. As the BN model outperformed the PLS-DA model in both accuracy and decreased risk of overfitting, it may therefore represent a viable alternative to typical analytical approaches for the investigation of metabolomics data. [ABSTRACT FROM AUTHOR]

Rationale: The relationship between longitudinal lung function trajectories, chest computed tomography (CT) imaging, and genetic predisposition to chronic obstructive pulmonary disease (COPD) has not been explored.Objectives: 1) To model trajectories using a data-driven approach applied to longitudinal data spanning adulthood in the Normative Aging Study (NAS), and 2) to apply these models to demographically similar subjects in the COPDGene (Genetic Epidemiology of COPD) Study with detailed phenotypic characterization including chest CT.Methods: We modeled lung function trajectories in 1,060 subjects in NAS with a median follow-up time of 29 years. We assigned 3,546 non-Hispanic white males in COPDGene to these trajectories for further analysis. We assessed phenotypic and genetic differences between trajectories and across age strata.Measurements and Main Results: We identified four trajectories in NAS with differing levels of maximum lung function and rate of decline. In COPDGene, 617 subjects (17%) were assigned to the lowest trajectory and had the greatest radiologic burden of disease (P < 0.01); 1,283 subjects (36%) were assigned to a low trajectory with evidence of airway disease preceding emphysema on CT; 1,411 subjects (40%) and 237 subjects (7%) were assigned to the remaining two trajectories and tended to have preserved lung function and negligible emphysema. The genetic contribution to these trajectories was as high as 83% (P = 0.02), and membership in lower lung function trajectories was associated with greater parental histories of COPD, decreased exercise capacity, greater dyspnea, and more frequent COPD exacerbations.Conclusions: Data-driven analysis identifies four lung function trajectories. Trajectory membership has a genetic basis and is associated with distinct lung structural abnormalities. [ABSTRACT FROM AUTHOR]

Obesity is associated with higher cardio-metabolic risk even in childhood and adolescence; whether this association is mediated by epigenetic mechanisms remains unclear. We examined the extent to which mid-childhood body mass index (BMI) z-score (median age 7.7 years) was associated with cardio-metabolic risk score in early adolescence (median age 12.9 years) via mid-childhood DNA methylation among 265 children in the Project Viva. We measured DNA methylation in leukocytes using the Infinium Human Methylation450K BeadChip. We assessed mediation CpG-by-CpG using epigenome-wide association analyses, high-dimensional mediation analysis, and natural effect models. We observed mediation by mid-childhood DNA methylation at 6 CpGs for the association between mid-childhood BMI z-score and cardio-metabolic risk score in early adolescence in the high-dimensional mediation analysis (accounting for 10% of the total effect) and in the natural effect model (β = 0.04, P = 3.2e-2, accounting for 13% of the total effect). The natural direct effect of BMI z-score on cardio-metabolic risk score was still evident (β = 0.27, P = 1.1e-25). We also observed mediation by mid-childhood DNA methylation at 5 CpGs that was in the opposite direction from the total effect (natural effect model: β = −0.04, P = 2.0e-2). Mediation in different directions implies a complex role of DNA methylation in the association between BMI and cardio-metabolic risk and needs further investigation. Future studies with larger sample size and greater variability in cardio-metabolic risk will further help elucidate the role of DNA methylation for cardio-metabolic risk. [ABSTRACT FROM AUTHOR]

DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV1, FEF25-75%) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly. [ABSTRACT FROM AUTHOR]

Summary: Background: Identifying metabolomic profiles of children with asthma has the potential to increase understanding of asthma pathophysiology. Objective: To identify differences in plasma metabolites between children with and without current asthma at mid‐childhood. Methods: We used untargeted mass spectrometry to measure plasma metabolites in 237 children (46 current asthma cases and 191 controls) in Project Viva, a birth cohort from eastern Massachusetts, USA. Current asthma was assessed at mid‐childhood (mean age 8.0 years). The ability of a broad spectrum metabolic profile to distinguish between cases and controls was assessed using partial least squares discriminant analysis. We used logistic regression models to identify individual metabolites that were differentially abundant by case–control status. We tested significant metabolites for replication in 411 children from the VDAART clinical trial. Results: There was no evidence of a systematic difference in the metabolome of children reporting current asthma vs. healthy controls according to partial least squares discriminant analysis. However, several metabolites were associated with odds of current asthma at a nominally significant threshold (P < .05), including a metabolite of nicotinamide (N1‐Methyl‐2‐pyridone‐5‐carboxamide (Odds Ratio (OR) = 2.8 (95% CI 1.1‐8.0)), a pyrimidine metabolite (5,6‐dihydrothymine (OR = 0.4 (95% CI 0.2‐0.9)), bile constituents (biliverdin (OR = 0.4 (95%CI 0.1‐0.9), taurocholate (OR = 2.0 (95% CI 1.2‐3.4)), two peptides likely derived from fibrinopeptide A (ORs from 1.6 to 1.7), and a gut microbiome metabolite (p‐cresol sulphate OR = 0.5 (95% CI 0.2‐0.9)). The associations for N1‐Methyl‐2‐pyridone‐5‐carboxamide and p‐cresol sulphate replicated in the independent VDAART population (one‐sided P values = .03‐.04). Conclusions and Clinical Relevance: Current asthma is nominally associated with altered levels of several metabolites, including metabolites in the nicotinamide pathway, and a bacterial metabolite derived from the gut microbiome. [ABSTRACT FROM AUTHOR]

BACKGROUND: Epigenetic variability is hypothesized as a regulatory pathway through which prenatal exposures may influence child development and health. OBJECTIVE: We sought to examine the associations of residential proximity to roadways at birth and epigenome-wide DNA methylation. We also assessed associations of differential methylation with child cognitive outcomes. METHODS: We estimated residential proximity to roadways at birth using a geographic information system (GIS) and cord blood methylation using Illumina's HumanMethylation450-array in 482 mother-child pairs in Project Viva. We identified individual CpGs associated with residentialproximity- to-roadways at birth using robust linear regression [false discovery rate ðFDRÞ<0:05]. We also estimated association between proximityto- roadways at birth and methylation of the same sites in blood samples collected at age 7-11 y (N=415). We ran the same analyses in the Generation R Study for replication (N=641). In Project Viva, we investigated associations of differential methylation at birth with midchildhood cognition using linear regression. RESULTS: Living closer to major roadways at birth was associated with higher cord blood (and--more weakly--midchildhood blood) methylation of four sites in LAMB2. For each halving of residential-proximity-to-major-roadways, we observed a 0.82% increase in DNA methylation at cg05654765 [95% confidence interval (CI): (0.54%, 1.10%)], 0.88% at cg14099457 [95% CI: (0.56%, 1.19%)], 0.19% at cg03732535 [95% CI: (0.11%, 0.28)], and 1.08% at cg02954987 [95% CI: (0.65%, 1.51%)]. Higher cord blood methylation of these sites was associated with lower midchildhood nonverbal cognitive scores. Our results did not replicate in the Generation R Study. CONCLUSIONS: Our discovery results must be interpreted with caution, given that they were not replicated in a separate cohort. However, living close to major roadways at birth was associated with cord blood methylation of sites in LAMB2--a gene known to be linked to axonal development--in our U.S. cohort. Higher methylation of these sites associated with lower nonverbal cognitive scores at age 7-11 y in the same children. [ABSTRACT FROM AUTHOR]

Prenatal folic acid exposure has been linked to higher risk of childhood asthma in countries that do not fortify the food supply with folic acid. This study seeks to examine this association in the United States, where the food supply is generally fortified with folic acid. Participants were 1279 mother-child pairs from Project Viva, an ongoing prospective birth cohort, with folic acid intake in pregnancy assessed through validated food frequency questionnaires. The primary outcome was physician-diagnosed asthma at mid-childhood. In an unadjusted logistic regression model, higher folic acid intake was associated with lower odds of asthma in mid-childhood (odds ratio [OR] 0.48; 95% CI 0.31-0.76). However, in the adjusted analysis this association was attenuated (adjusted OR [aOR] 0.80; 95% CI 0.49-1.33). Our results suggest that in the United States, where there is generalized folic acid fortification of food, maternal folic acid intake during pregnancy is not associated with asthma development in offspring. [ABSTRACT FROM AUTHOR]

Rationale: Cross-sectional studies have linked intake of high-fructose corn syrup-sweetened beverages with asthma in schoolchildren.Objectives: To examine associations of maternal prenatal and early childhood intake of sugar-sweetened beverages and fructose with current asthma in midchildhood (median age, 7.7 yr).Methods: We assessed maternal pregnancy (first- and second-trimester average) and child (median age, 3.3 yr) intake of sugar-sweetened beverages and total fructose using food frequency questionnaires in 1,068 mother-child pairs from Project Viva, a prospective prebirth cohort. In a multivariable analysis, we examined associations of quartiles of maternal and child sugar-sweetened beverage, juice, and total fructose intake with child current asthma in midchildhood, assessed by questionnaire as ever having doctor-diagnosed asthma plus taking asthma medications or reporting wheezing in the past 12 months.Results: Higher maternal pregnancy sugar-sweetened beverage consumption (mean, 0.6 servings/d; range, 0-5) was associated with younger maternal age, nonwhite race/ethnicity, lower education and income, and higher prepregnancy body mass index. Adjusting for prepregnancy body mass index and other covariates, comparing quartile 4 with quartile 1, higher maternal pregnancy intake of sugar-sweetened beverages (odds ratio, 1.70; 95% confidence interval, 1.08-2.67) and total fructose (odds ratio, 1.58; 95% confidence interval, 0.98-2.53) were associated with greater odds of midchildhood current asthma (prevalence, 19%). Higher early childhood fructose intake (quartile 4 vs. quartile 1) was also associated with midchildhood current asthma in models adjusted for maternal sugar-sweetened beverages (odds ratio, 1.79; 95% confidence interval, 1.07-2.97) and after additional adjustment for midchildhood body mass index z-score (odds ratio, 1.77; 95% confidence interval, 1.06-2.95).Conclusions: Higher sugar-sweetened beverage and fructose intake during pregnancy and in early childhood was associated with childhood asthma development independent of adiposity. [ABSTRACT FROM AUTHOR]

Background Alterations in the intestinal microbiome are prospectively associated with the development of asthma; less is known regarding the role of microbiome alterations in food allergy development. Methods Intestinal microbiome samples were collected at age 3-6 months in children participating in the follow-up phase of an interventional trial of high-dose vitamin D given during pregnancy. At age 3, sensitization to foods (milk, egg, peanut, soy, wheat, walnut) was assessed. Food allergy was defined as caretaker report of healthcare provider-diagnosed allergy to the above foods prior to age 3 with evidence of IgE sensitization. Analysis was performed using Phyloseq and DESeq2; P-values were adjusted for multiple comparisons. Results Complete data were available for 225 children; there were 87 cases of food sensitization and 14 cases of food allergy. Microbial diversity measures did not differ between food sensitization and food allergy cases and controls. The genera Haemophilus (log2 fold change −2.15, P=.003), Dialister (log2 fold change −2.22, P=.009), Dorea (log2 fold change −1.65, P=.02), and Clostridium (log2 fold change −1.47, P=.002) were underrepresented among subjects with food sensitization. The genera Citrobacter (log2 fold change −3.41, P=.03), Oscillospira (log2 fold change −2.80, P=.03), Lactococcus (log2 fold change −3.19, P=.05), and Dorea (log2 fold change −3.00, P=.05) were underrepresented among subjects with food allergy. Conclusions The temporal association between bacterial colonization and food sensitization and allergy suggests that the microbiome may have a causal role in the development of food allergy. Our findings have therapeutic implications for the prevention and treatment of food allergy. [ABSTRACT FROM AUTHOR]