Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

The Legacy of Redlining: Increasing Childhood Asthma Disparities Through Neighborhood Poverty.

RATIONALE: Identifying the root causes of racial disparities in childhood asthma is critical for health equity. OBJECTIVES: To determine if the 1930's racist policy of redlining led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP). METHODS: We categorized census tracts at birth of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into A, B, C, or D categories as defined by the Home Owners Loan Corporation (HOLC), with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract including the percentage of low-income households, the CDC's social vulnerability index (SVI), and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through census tract-level mediators adjusting for individual-level covariates. MEASUREMENTS AND MAIN RESULTS: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6% and 13.2% resided in census tracts with a HOLC grade of D. In mediation analyses, residing in grade D tracts (aOR = 1.03 [95%CI 1.01,1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for SVI and other tract-level variables. CONCLUSIONS: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

Effect of Daily Vitamin D Supplementation on Risk of Upper Respiratory Infection in Older Adults: A Randomized Controlled Trial.

BACKGROUND: Among individuals with vitamin D deficiency, daily vitamin D supplementation appears to lower risk of acute respiratory infection. However, recent trials, in different populations and using different regimens, have yielded null results. We investigated the effect of daily vitamin D supplementation (vs placebo) on risk of upper respiratory infection (URI) in older adults. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, double-blind, placebo-controlled trial of supplemental vitamin D and/or omega-3 fatty acids in generally healthy men (age ≥50 years) and women (age ≥55 years). This prespecified analysis focuses on vitamin D3 (2000 IU/day) versus placebo in the 15 804 (61%) participants with baseline serum total 25-hydroxyvitamin D level. The primary outcome was self-report of a recent URI at 1-year follow-up. RESULTS: Participants had a mean age of 68 years and 51% were women; 76% were non-Hispanic White, 16% Black, and 8% other race/ethnicity. The mean 25-hydroxyvitamin D level at baseline was 31 (standard deviation, 10) ng/mL, with <12 ng/mL in 2.4%. The overall effect of vitamin D supplementation on recent URI was nonsignificant (odds ratio [OR], 0.96 [95% confidence interval {CI}, .86-1.06]). In the prespecified subgroup of primary interest (<12 ng/mL and denied taking concurrent vitamin D), which had only 255 participants, vitamin D supplementation was nonsignificant (OR, 0.60 [95% CI, .28-1.30]). Statistical power to assess effect modification in other subgroups was limited. CONCLUSIONS: In older adults not selected for vitamin D deficiency, supplemental vitamin D did not lower URI risk overall. Whether effects differ in subgroups requires further study. Clinical Trials Registration. NCT01169259.

Relative humidity, temperature, and hypertensive disorders of pregnancy: Findings from the Project Viva cohort.

BACKGROUND: Preeclampsia is a multi-system hypertensive disorder of pregnancy that is a leading cause of maternal and fetal morbidity and mortality. Prior studies disagree on the cause and even the presence of seasonal patterns in its incidence. Using unsuitable time windows for seasonal exposures can bias model results, potentially explaining these inconsistencies. OBJECTIVES: We aimed to investigate humidity and temperature as possible causes for seasonal trends in preeclampsia in Project Viva, a prebirth cohort in Boston, Massachusetts, considering only exposure windows that precede disease onset. METHODS: Using the Parameter-elevation Relationships on Independent Slopes Model (PRISM) Climate Dataset, we estimated daily residential temperature and relative humidity (RH) exposures during pregnancy. Our primary multinomial regression adjusted for person-level covariates and season. Secondary analyses included distributed lag models (DLMs) and adjusted for ambient air pollutants including fine particulates (PM2.5). We used Generalized Additive Mixed Models (GAMMs) for systolic blood pressure (SBP) trajectories across hypertensive disorder statuses to confirm exposure timing. RESULTS: While preeclampsia is typically diagnosed late in pregnancy, GAMM-fitted SBP trajectories for preeclamptic and non-preeclamptic women began to diverge at around 20 weeks' gestation, confirming the need to only consider early exposures. In the primary analysis with 1776 women, RH in the early second trimester, weeks 14-20, was associated with significantly higher odds of preeclampsia (OR per IQR increase: 1.81, 95% CI: 1.10, 2.97). The DLM corroborated this window, finding a positive association from weeks 12-20. There were no other significant associations between RH or temperature and preeclampsia or gestational hypertension in any other time period. DISCUSSION: The association between preeclampsia and RH in the early second trimester was robust to model choice, suggesting that RH may contribute to seasonal trends in preeclampsia incidence. Differences between these results and those of prior studies could be attributable to exposure timing differences.

Prenatal blood metals, per- and polyfluoroalkyl substances and antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion.

BACKGROUND: Evidence suggests that prenatal per- and polyfluoroalkyl substances (PFAS) and metals, two classes of chemicals found ubiquitously in human populations, influence immune system development and response. OBJECTIVE: We evaluated whether first trimester blood PFAS and metals were associated with antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion. METHODS: We measured six PFAS, as well as six nonessential and four essential metals, in first trimester blood from participants in the longitudinal pre-birth Project Viva cohort, recruited between 1999-2000 in eastern Massachusetts. We measured antigen- or mitogen-stimulated cord blood mononuclear cell proliferation responses (n=269-314) and cytokine secretion (n=217-302). We used covariate-adjusted least absolute shrinkage and selection operator (LASSO) for variable selection and multivariable regression to estimate associations with the immune markers. RESULTS: Each ng/mL of MeFOSAA was associated with a 3.6% (1.4, 5.8) higher lymphocyte proliferation response after stimulation with egg antigen, as well as 0.8 (0.7, 1.0) reduced odds of having IFN-γ detected in response to dust mite. Each ng/g increment of cesium was associated with 27.8% (-45.1, -4.9) lower IL-10 levels in response to dust mite. Each ng/g increment of mercury was associated with 12.0% (1.3, 23.8) higher IL-13 levels in response to mitogen PHA. Each ng/g increment of selenium and zinc was associated with 0.2% (0.01, 0.4) and 0.01% (0.002, 0.02) higher TNF-α in response to mitogen PHA, respectively. CONCLUSIONS: Prenatal metals and PFAS influence cord blood lymphocyte proliferation and cytokine secretion in ways that may increase risk for atopic disease in childhood.

Prediction of internalizing and externalizing symptoms in late childhood from attention-deficit/hyperactivity disorder symptoms in early childhood.

Limited analyses based on national samples have assessed whether early attention-deficit/hyperactivity disorder (ADHD) symptoms predict later internalizing and externalizing symptoms in youth and the influence of sex and pubertal timing on subsequent psychiatric symptoms. This study analyzed data (n = 2818) from the Environmental influences on Child Health Outcomes Program national cohort. Analyses used data from early childhood (mean age = 5.3 years) utilizing parent-reported ADHD symptoms to predict rates of internalizing and externalizing symptoms from late childhood/adolescence (mean age = 11.9 years). Within a subsample age at peak height velocity (APHV) acted as a proxy to assess pubertal timing from early childhood (mean age = 5.4 years) to adolescence (mean age = 12.3 years). Early-childhood ADHD symptoms predicted later psychiatric symptoms, including anxiety, depression, aggressive behavior, conduct problems, oppositional defiant disorder, and rule-breaking behavior. Earlier APHV was associated with increased Conduct Disorder symptoms from late childhood to adolescence for females only. A stronger relation between ADHD symptoms and later aggression was observed in females with earlier APHV, whereas this same pattern with aggression, conduct problems and depression was observed in males with later APHV. Clinicians should consider that both young girls and boys with elevated ADHD symptoms, particularly with off-set pubertal timing, may be at risk for later psychiatric symptoms.

A comparison of caregiver-reported snoring and objective snoring in children from urban neighborhoods.

OBJECTIVE: Sleep Disordered Breathing (SDB) is both prevalent and under-recognized in pediatric minority populations. Recognition of SDB is often triggered by symptoms of caregiver-reported snoring. However, the validity and utility of caregiver reports likely vary across populations. Our objective is to assess the association between caregiver-reported snoring and objectively recorded snoring in a low-income urban community and explore factors associated with agreement between objective and subjective snoring. METHODS: 169 6 to 12 year old participants underwent at-home sleep studies with a WatchPAT device as part of the Environmental Assessment of Sleep in Youth (EASY) cohort study. Differences in subjective snoring, objective snoring, and concordance between subjective and objective snoring based on socioeconomic and clinical characteristics were assessed. RESULTS: The sample had a high proportion of non-white (78.9 %) and low income (39.6 %) children. Caregivers reported snoring for 20.7 % of the children and snoring was measured objectively for 21.9 %. Of those with objective snoring, only 29.7 % were identified as snorers by caregiver report (sensitivity: 0.30; specificity: 0.82). Primary Spanish language and co-sleeping were associated with increased caregiver reported snoring, and allergy was associated with increased objective snoring. Older child age and normal range BMI percentile were associated with higher concordance between caregiver and objective snoring. CONCLUSIONS: Among a community-based, predominantly minority sample, caregiver-reported snoring resulted in under-estimation of prevalence of objectively assessed snoring. Reliance on caregiver report may poorly identify children with snoring or SDB in clinical practice.

Climate change is a health crisis with opportunities for health care action: A focus on health care providers, patients with asthma and allergic immune diseases, and their families and neighbors.

Climate change has increased the frequency of extreme weather events and compounded natural disasters. Heat, wildfires, flooding, and pollen are already threatening public health and disproportionately affecting individuals in susceptible situations and vulnerable locations. In this theme issue of the Journal of Allergy and Clinical Immunology, we address what is known and not known about the biologic as well as clinical upstream and downstream effects of climate change on asthma and allergy development and exacerbation. We present potential actions that individuals can take at the family, neighborhood, community, health care system, and national and international levels to build climate resilience and protect their own health and the health and welfare of others. We emphasize the importance of actions and policies that are context specific and just. We emphasize the need for the health care system, which contributes between 3% and 5% of global greenhouse gas emissions, to reduce its carbon footprint and build resiliency. Health care providers play a pivotal role in helping policymakers understand the effects of climate on the health of our patients. There is still a window to avoid the most serious effects of climate change on human health and our planet.

Incidence rates of childhood asthma with recurrent exacerbations in the US Environmental influences on Child Health Outcomes (ECHO) program.

BACKGROUND: Descriptive epidemiological data on incidence rates (IRs) of asthma with recurrent exacerbations (ARE) are sparse. OBJECTIVES: This study hypothesized that IRs for ARE would vary by time, geography, age, and race and ethnicity, irrespective of parental asthma history. METHODS: The investigators leveraged data from 17,246 children born after 1990 enrolled in 59 US with 1 Puerto Rican cohort in the Environmental Influences on Child Health Outcomes (ECHO) consortium to estimate IRs for ARE. RESULTS: The overall crude IR for ARE was 6.07 per 1000 person-years (95% CI: 5.63-6.51) and was highest for children aged 2-4 years, for Hispanic Black and non-Hispanic Black children, and for those with a parental history of asthma. ARE IRs were higher for 2- to 4-year-olds in each race and ethnicity category and for both sexes. Multivariable analysis confirmed higher adjusted ARE IRs (aIRRs) for children born 2000-2009 compared with those born 1990-1999 and 2010-2017, 2-4 versus 10-19 years old (aIRR = 15.36; 95% CI: 12.09-19.52), and for males versus females (aIRR = 1.34; 95% CI 1.16-1.55). Black children (non-Hispanic and Hispanic) had higher rates than non-Hispanic White children (aIRR = 2.51; 95% CI 2.10-2.99; and aIRR = 2.04; 95% CI: 1.22-3.39, respectively). Children born in the Midwest, Northeast and South had higher rates than those born in the West (P < .01 for each comparison). Children with a parental history of asthma had rates nearly 3 times higher than those without such history (aIRR = 2.90; 95% CI: 2.43-3.46). CONCLUSIONS: Factors associated with time, geography, age, race and ethnicity, sex, and parental history appear to influence the inception of ARE among children and adolescents.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics).

Neighborhood Conditions and Resources in Mid-Childhood and Dampness and Pests at Home in Adolescence.

OBJECTIVE: To examine prospectively associations of neighborhood opportunity with the presence of dampness or pests in the home environment during early adolescence. STUDY DESIGN: We geocoded residential addresses from 831 children (mean age 7.9 years, 2007-2011) in the Project Viva cohort. We linked each address with census tract-level Child Opportunity Index scores, which capture neighborhood conditions and resources influencing child heath including educational, health, environmental, and socioeconomic factors. Our primary outcome was presence of dampness or pests in the home in early adolescence (mean age 13.2 years, 2013-2016). Secondary outcomes included current asthma and lung function testing results. Mixed-effects regression models estimated longitudinal associations of Child Opportunity Index scores with outcomes, adjusting for individual and family sociodemographics. RESULTS: Children residing in neighborhoods with greater overall opportunity were less likely to live in homes with dampness or pests approximately 5 years later (aOR 0.85 per 20-unit increase in Child Opportunity Index percentile rank, 95% CI 0.73-0.998). We observed no significant associations in adjusted models of overall neighborhood opportunity with current asthma or lung function. Lower school poverty or single-parent households and greater access to healthy food or economic resource index were associated with lower odds of a home environment with dampness or pests. CONCLUSIONS: More favorable neighborhood conditions in mid-childhood were associated with lower likelihood of living in a home with dampness or pests in the early adolescence.

Early-life fecal metabolomics of food allergy.

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.

The maternal prenatal and offspring early-life gut microbiome of childhood asthma phenotypes.

BACKGROUND: The infant fecal microbiome is known to impact subsequent asthma risk, but the environmental exposures impacting this association, the role of the maternal microbiome, and how the microbiome impacts different childhood asthma phenotypes are unknown. METHODS: Our objective was to identify associations between features of the prenatal and early-life fecal microbiomes and child asthma phenotypes. We analyzed fecal 16 s rRNA microbiome profiling and fecal metabolomic profiling from stool samples collected from mothers during the third trimester of pregnancy (n = 120) and offspring at ages 3-6 months (n = 265), 1 (n = 436) and 3 years (n = 506) in a total of 657 mother-child pairs participating in the Vitamin D Antenatal Asthma Reduction Trial. We used clinical data from birth to age 6 years to characterize subjects with asthma as having early, transient or active asthma phenotypes. In addition to identifying specific genera that were robustly associated with asthma phenotypes in multiple covariate-adjusted models, we clustered subjects by their longitudinal microbiome composition and sought associations between fecal metabolites and relevant microbiome and clinical features. RESULTS: Seven maternal and two infant fecal microbial taxa were robustly associated with at least one asthma phenotype, and a longitudinal gut microenvironment profile was associated with early asthma (Fisher exact test p = .03). Though mode of delivery was not directly associated with asthma, we found substantial evidence for a pathway whereby cesarean section reduces fecal Bacteroides and microbial sphingolipids, increasing susceptibility to early asthma. CONCLUSION: Overall, our results suggest that the early-life, including prenatal, fecal microbiome modifies risk of asthma, especially asthma with onset by age 3 years.

HEPA filtration intervention in classrooms may improve some students' asthma.

OBJECTIVE: The School Inner-City Asthma Intervention Study 2 (SICAS 2) tested interventions to reduce exposures in classrooms of students with asthma. The objective of this post-hoc analysis was limited to evaluating the effect of high-efficiency particulate (HEPA) filtration interventions on mold levels as quantified using the Environmental Relative Moldiness Index (ERMI) and the possible improvement in the students' asthma, as quantified by spirometry testing. METHODS: Pre-intervention dust samples were collected at the beginning of the school year from classrooms and corresponding homes of students with asthma (n = 150). Follow-up dust samples were collected in the classrooms at the end of the HEPA or Sham intervention. For each dust sample, ERMI values and the Group 1 and Group 2 mold levels (components of the ERMI metric) were quantified. In addition, each student's lung function was evaluated by spirometry testing, specifically the percentage predicted forced expiratory volume at 1 sec (FEV1%), before and at the end of the intervention. RESULTS: For those students with a higher Group 1 mold level in their pre-intervention classroom than home (n = 94), the FEV1% results for those students was significantly (p < 0.05) inversely correlated with the Group 1 level in their classrooms. After the HEPA intervention, the average Group 1 and ERMI values were significantly lowered, and the average FEV1% test results significantly increased by an average of 4.22% for students in HEPA compared to Sham classrooms. CONCLUSIONS: HEPA intervention in classrooms reduced Group 1 and ERMI values, which corresponded to improvements in the students' FEV1% test results.

The role of short-term air pollution and temperature on arterial stiffness in a longitudinal closed cohort of elderly individuals.

BACKGROUND/AIMS: Our study adds to the sparse literature that examines whether arterial stiffness, related to cardiovascular risk, increases with exposure to air pollution. We assessed the associations between spatiotemporally resolved air pollutants and vascular and hemodynamic parameters in an elderly population-based in Eastern Massachusetts. METHODS: Among 397 men living in Eastern Massachusetts between 2007 and 2013, we utilized time-varying linear mixed-effects regressions to examine associations between central augmentation index (%) and central pulse pressure (mmHg) and short-term (0-7 days) exposure to air pollution concentrations (fine particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3)), and temperature adjusted for known cardiovascular risk factors. Central augmentation index (AIx) and pulse pressure (AP) were measured at each visit using radial artery applanation tonometry for pulse wave analysis. Each air pollutant and temperature were geocoded to the participant's residential address using validated ensemble and hybrid exposure models and gridMET predictions. RESULTS: We found consistent results that higher short-term PM2.5 concentrations (0-7 day moving averages) were associated with significantly higher measures of arterial stiffness. Each 4.52 µg/m3 interquartile range (IQR) increase in daily PM2.5 for a 3-day moving average was associated with a 0.63% (95% confidence interval (CI): 0.11, 1.15) increase in AIx and a 1.65 mmHg (95% CI: 0.42, 2.88) increase in pulse pressure. Furthermore, each 3.83 µg/m3 IQR increase in daily PM2.5 for a 7-day moving average was associated with a 0.57% (95% CI: -0.01, 1.14) increase in AIx and a 1.91 mmHg (95% CI: 0.54, 3.28) increase in pulse pressure. Smaller increases in AIx and AP were observed for the other short-term moving averages of PM2.5 exposure apart from days zero and five for AIx. We found no clear association between O3, NO2, temperature, and the outcomes. CONCLUSIONS: Short-term PM2.5 exposure was associated with markers of arterial stiffness and central hemodynamics.

Delayed egg introduction beyond infancy and increased egg allergy risk in childhood.

AIM: Egg is a major food allergen in childhood. Recent studies suggest that early introduction of allergenic foods can decrease the risk of developing egg allergy. The impact of early egg introduction in the general population is unclear. We examined associations between age of infant egg introduction and childhood egg allergy outcomes in a general population. METHODS: The study population consisted of 1217 neonates from Project Viva, a longitudinal pre-birth cohort in eastern Massachusetts area, USA. Mothers reported age of infant egg introduction and child egg allergy using questionnaires and specific IgE to egg white was assayed. We estimated associations between age of infant egg introduction and egg allergy outcomes using Log-binomial regression models, adjusting for socio-demographics and health confounders. RESULTS: Egg allergy at 2 years was significantly higher (8.0% vs. 1.4%, P < 0.0001) in children who had delayed egg introduction beyond infancy, compared with children who were introduced to egg during infancy (adjusted relative risk or aRR 7.58; 95% CI 3.08, 18.61). At 12 years, the risk of egg allergy remained significantly higher (3.9% vs. 1.1%, P = 0.048) in children with delayed egg introduction compared with children introduced to egg during infancy (aRR 4.07; 95% CI 1.20, 13.87). CONCLUSIONS: Infants with delayed introduction of eggs after 12 months had increased risk of egg allergy in childhood (2 years) and the relationship persisted in early adolescence (12 years). Our findings suggest that introduction to eggs before 12 months could contribute to the prevention of egg allergy.

Association of the gut microbiome and metabolome with wheeze frequency in childhood asthma.

BACKGROUND: While the microbiome has an established role in asthma development, less is known about its contribution to morbidity in children with asthma. OBJECTIVE: In this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we analyzed the gut microbiome and metabolome of wheeze frequency in children with asthma. METHODS: Bacterial 16S ribosomal RNA microbiome and untargeted metabolomic profiling were performed on fecal samples collected from 3-year-old children with parent-reported physician-diagnosed asthma. We analyzed wheeze frequency by calculating the proportion of quarterly questionnaires administered between ages 3 and 5 years in which parents reported the child had wheezed (wheeze proportion). Taxa and metabolites associated with wheeze were analyzed by identifying log fold changes with respect to wheeze frequency and correlation/linear regression analyses, respectively. Microbe-metabolite and microbe-microbe correlation networks were compared between subjects with high and low wheeze proportion. RESULTS: Specific taxa, including the genus Veillonella and histidine pathway metabolites, were enriched in subjects with high wheeze proportion. Among wheeze-associated taxa, Veillonella and Oscillospiraceae UCG-005, which was inversely associated with wheeze, were correlated with the greatest number of fecal metabolites. Microbial networks were similar between subjects with low versus high wheeze frequency. CONCLUSION: Gut microbiome features are associated with wheeze frequency in children with asthma, suggesting an impact of the gut microbiome on morbidity in childhood asthma.

The Role of Childhood Asthma in Obesity Development: A Nationwide US Multicohort Study.

RATIONALE: Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset. OBJECTIVES: To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association. METHODS: We studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years). MEASUREMENTS AND MAIN RESULTS: We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23). CONCLUSIONS: This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

Solar and geomagnetic activity enhance the effects of air pollutants on atrial fibrillation.

AIMS: Cardiac arrhythmias have been associated with intense solar and geomagnetic activity (SGA) and exposures to air pollution. METHODS AND RESULTS: We examined whether oscillations of SGA can modify the effect of hourly exposures to air pollutants on atrial fibrillation ≥30 s (AF) risk in patients with dual-chamber implantable cardioverter-defibrillators. The effects of SGA on ambient particulate matter <2.5 µm (PM2.5), black carbon (BC), ultrafine particles (PN), and associations with AF were assessed. Measures of SGA included solar wind proton density (SW), total interplanetary magnetic field strength (IMF), and Kp index, a measure of global geomagnetic activity. Overall time lags between 0 and 24 h, periods of increased SGA (>50th percentile in IMF, SW, and Kp index) enhanced the effects of all three air pollutants on AF, while during periods of reduced SGA the associations were considerably weaker or absent. During periods of intense SW 6 h prior to an AF event, the odds ratio (OR) for PM2.5 exposure per interquartile range (IQR) of 5.6 µg/m3 was 1.7 [95% confident interval (CI) 1.3-2.3, P = 0.0001]. For periods of reduced SW, the OR for PM2.5 exposure per IQR was 1.2 (95% CI 0.9-1.5; P = 0.27). There were similar effects for PN and BC exposures. In patients with multiple AF events per hour, the associations with air pollutants during intense SGA were even greater. CONCLUSION: The effects of air pollutants up to 24 h before AF events were enhanced during periods of increased SGA. Our results suggest that these effects may account for variation in AF risk.

Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood.

Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry.Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children.Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children.Conclusions: These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.