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Prior studies suggest that vitamin D may modify the effects of environmental exposures; however, none have investigated gestational vitamin D and cumulative tobacco smoke exposure (TSE) throughout pregnancy and early life.This study investigated the effects of early life TSE on child lung function and the modulatory effects of gestational vitamin D on this association.The VDAART (Vitamin D Antenatal Asthma Reduction Trial) recruited nonsmoking pregnant women and followed the mother-child pairs to age 6 years. TSE was assessed with questionnaires and plasma cotinine measurements in the mothers (10-18 and 32-38 gestational weeks) and children (1, 3, and 6 years). Cumulative TSE was calculated from the repeated cotinine measurements. 25-hydroxyvitamin D (25[OH]D) levels were measured at 10-18 and 32-38 gestational weeks. Lung function was assessed at 6 years with spirometry and impulse oscillometry.Of the 476 mother-child pairs, 205 (43%) had increased cotinine levels at ≥1 time point. Cumulative TSE was associated with decreased FEVCumulative TSE from pregnancy to childhood is associated with dose- and duration-dependent decreases in child lung function at 6 years even in the absence of reported maternal smoking. Gestational vitamin D may modulate this effect and have therapeutic potential for minimizing the adverse effect of TSE on lung throughout early life.Maternal Vitamin D Supplementation to Prevent Childhood Asthma (VDAART); clinicaltrials.gov identifier: NCT00920621.

While the microbiome has an established role in asthma development, less is known about its contribution to morbidity in children with asthma.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.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.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.Gut microbiome features are associated with wheeze frequency in children with asthma, suggesting an impact of the gut microbiome on morbidity in childhood asthma.

Whether children and people with asthma and allergic diseases are at increased risk for severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection is unknown.Our aims were to determine the incidence of SARS-CoV-2 infection in households with children and to also determine whether self-reported asthma and/or other allergic diseases are associated with infection and household transmission.For 6 months, biweekly nasal swabs and weekly surveys were conducted within 1394 households (N = 4142 participants) to identify incident SARS-CoV-2 infections from May 2020 to February 2021, which was the pandemic period largely before a vaccine and before the emergence of SARS-CoV-2 variants. Participant and household infection and household transmission probabilities were calculated by using time-to-event analyses, and factors associated with infection and transmission risk were determined by using regression analyses.In all, 147 households (261 participants) tested positive for SARS-CoV-2. The household SARS-CoV-2 infection probability was 25.8%; the participant infection probability was similar for children (14.0% [95% CI = 8.0%-19.6%]), teenagers (12.1% [95% CI = 8.2%-15.9%]), and adults (14.0% [95% CI = 9.5%-18.4%]). Infections were symptomatic in 24.5% of children, 41.2% of teenagers, and 62.5% of adults. Self-reported doctor-diagnosed asthma was not a risk factor for infection (adjusted hazard ratio [aHR] = 1.04 [95% CI = 0.73-1.46]), nor was upper respiratory allergy or eczema. Self-reported doctor-diagnosed food allergy was associated with lower infection risk (aHR = 0.50 [95% CI = 0.32-0.81]); higher body mass index was associated with increased infection risk (aHR per 10-point increase = 1.09 [95% CI = 1.03-1.15]). The household secondary attack rate was 57.7%. Asthma was not associated with household transmission, but transmission was lower in households with food allergy (adjusted odds ratio = 0.43 [95% CI = 0.19-0.96]; P = .04).Asthma does not increase the risk of SARS-CoV-2 infection. Food allergy is associated with lower infection risk, whereas body mass index is associated with increased infection risk. Understanding how these factors modify infection risk may offer new avenues for preventing infection.

In the United States, Black and Hispanic children have higher rates of asthma and asthma-related morbidity compared with White children and disproportionately reside in communities with economic deprivation.To determine the extent to which neighborhood-level socioeconomic indicators explain racial and ethnic disparities in childhood wheezing and asthma.The study population comprised children in birth cohorts located throughout the United States that are part of the Children's Respiratory and Environmental Workgroup consortium. Cox proportional hazard models were used to estimate hazard ratios (HRs) of asthma incidence, and logistic regression was used to estimate odds ratios of early and persistent wheeze prevalence accounting for mother's education, parental asthma, smoking during pregnancy, child's race and ethnicity, sex, and region and decade of birth.Neighborhood-level socioeconomic indicators defined by US census tracts calculated as z scores for multiple tract-level variables relative to the US average linked to participants' birth record address and decade of birth. The parent or caregiver reported the child's race and ethnicity.Prevalence of early and persistent childhood wheeze and asthma incidence.Of 5809 children, 46% reported wheezing before age 2 years, and 26% reported persistent wheeze through age 11 years. Asthma prevalence by age 11 years varied by cohort, with an overall median prevalence of 25%. Black children (HR, 1.47; 95% CI, 1.26-1.73) and Hispanic children (HR, 1.29; 95% CI, 1.09-1.53) were at significantly increased risk for asthma incidence compared with White children, with onset occurring earlier in childhood. Children born in tracts with a greater proportion of low-income households, population density, and poverty had increased asthma incidence. Results for early and persistent wheeze were similar. In effect modification analysis, census variables did not significantly modify the association between race and ethnicity and risk for asthma incidence; Black and Hispanic children remained at higher risk for asthma compared with White children across census tracts socioeconomic levels.Adjusting for individual-level characteristics, we observed neighborhood socioeconomic disparities in childhood wheeze and asthma. Black and Hispanic children had more asthma in neighborhoods of all income levels. Neighborhood- and individual-level characteristics and their root causes should be considered as sources of respiratory health inequities.

Early-life viral infection can have profound effects on the developing lung and immune systems, both important in asthma development. For decades, research has aimed to establish whether there is a causal link between these viral infections as an exposure and asthma later in childhood. Establishing causality will remain important, but new insights regarding early-life viral infection as an exposure, the recognition of asthma as a heterogeneous outcome, and the shared genetic susceptibility to both suggest a refocus from answering the theoretical question of causality toward additional pragmatic approaches focusing on improving patient outcomes across the spectrum of respiratory disease. This Clinical Commentary reviews the evidence on the consequences of early-life viral infection and aims to look beyond the question of causality, suggesting a research agenda specifically aimed at what matters for human development, and for the quality of life of current and future patients with wheezing disorders.

Assessment of asthma comorbidities, conditions that adversely affect the pathobiology of asthma or impair its response to therapies, is a fundamental step in the evaluation and management of patients with difficult-to-treat asthma. Identifying and effectively treating asthma comorbidities, such as obesity, obstructive sleep apnea, and chronic sinusitis with nasal polyps may improve asthma control and reduce exacerbations. Additionally, identifying comorbid T2 inflammatory conditions may help guide optimal selection of biologic therapies. Here, we describe common comorbid conditions found in adult and pediatric difficult-to-control asthma, discuss evidence for the association with asthma morbidity and treatment benefit, and provide information on how and when to assess comorbidities.

Asthma is a common allergic airway disease that develops in association with the human microbiome early in life. Both the composition and function of the infant gut microbiota have been linked to asthma risk, but functional alterations in the gut microbiota of older patients with established asthma remain an important knowledge gap. Here, we performed whole metagenomic shotgun sequencing of 95 stool samples from 59 healthy and 36 subjects with moderate-to-severe asthma to characterize the metagenomes of gut microbiota in children and adults 6 years and older. Mapping of functional orthologs revealed that asthma contributes to 2.9% of the variation in metagenomic content even when accounting for other important clinical demographics. Differential abundance analysis showed an enrichment of long-chain fatty acid (LCFA) metabolism pathways which have been previously implicated in airway smooth muscle and immune responses in asthma. We also observed increased richness of antibiotic resistance genes (ARGs) in people with asthma. One differentially abundant ARG was a macrolide resistance marker,ermF, which significantly co-occurred with theBacteroides fragilistoxin, suggesting a possible relationship between enterotoxigenicB. fragilis, antibiotic resistance, and asthma. Lastly, we found multiple virulence factor (VF) and ARG pairs that co-occurred in both cohorts suggesting that virulence and antibiotic resistance traits are co-selected and maintained in the fecal microbiota of people with asthma. Overall, our results show functional alterations via LCFA biosynthetic genes and increases in antibiotic resistance genes in the gut microbiota of subjects with moderate-to-severe asthma and could have implications for asthma management and treatment.

Genetic factors and early-life exposures1 are both important determinants of childhood asthma. Among the more than 150 loci identified in genome-wide association studies (GWAS), 17q12-q21 is the most replicated childhood-onset asthma locus.2 Fine-mapping at this locus has been difficult in populations of European ancestry because of extensive linkage disequilibrium (LD) in this region. Taking advantage of the reduced LD in African ancestry populations, we3 and others4,5 have shown that single nucleotide polymorphisms (SNPs) in GSDMB are likely causal for childhood-onset asthma at this locus. However, it remains unclear whether the same variants underlie the many genotype-exposure interaction (GEI) effects.

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.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.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.Several classes of bioactive fecal metabolites are associated with food allergy and/or sensitization including bile acids, steroid hormones, sphingolipids, and caffeine metabolites.

Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function.We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma.We analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity.Greater baseline wall area percent (β = -0.15 [95% CI = -0.26 to -0.05]; P .01), hyperinflation percent (β = -0.25 [95% CI = -0.41 to -0.09]; P.01), and Jacobian gradient measurements (cranial-caudal β = 10.64 [95% CI = 3.79-17.49]; P .01; posterior-anterior β = -9.14, [95% CI = -15.49 to -2.78]; P .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio = 1.06 [95% CI = 1.01-1.10]; P = .02) and air trapping percent (rate ratio =1.01 [95% CI = 1.00-1.02]; P = .03), as well as lower decline in the Jacobian determinant mean (rate ratio = 0.58 [95% CI = 0.41-0.82]; P .01) and Jacobian determinant standard deviation (rate ratio = 0.52 [95% CI = 0.32-0.85]; P = .01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires.Baseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

BACKGROUND: The pathogenesis of childhood asthma is complex, and determinants of risk may begin in utero. OBJECTIVE: To describe the association of systemic prenatal inflammation, measured by plasma C-reactive protein (CRP), with childhood asthma, eczema, and allergic rhinitis. METHODS: A total of 522 maternal-offspring pairs from the Vitamin D Antenatal Asthma Reduction Trial were included. Prenatal plasma CRP level was measured between 10 and 18 weeks of gestation and between 32 and 38 weeks of gestation. Offspring asthma, eczema, and allergic rhinitis were assessed quarterly between birth and age 6 years. We performed mediation analyses of prenatal CRP on the association between several maternal characteristics and offspring asthma. RESULTS: Elevated early and late prenatal CRP and an increase in CRP from early to late pregnancy were associated with asthma by age 6 years (early: adjusted odds ratio [aOR], 1.76, 95% CI, 1.12-2.82, P = .02; late: aOR, 2.45, 95% CI, 1.47-4.18, P < .001; CRP increase: aOR, 2.06, 95% CI, 1.26-3.39, P < .004). Prenatal CRP and childhood asthma associations were strengthened among offspring with atopic asthma (early: aOR, 3.78, 95% CI, 1.49-10.64, P = .008; late: aOR, 4.84, 95% CI, 1.68-15.50, P = .005; CRP increase: aOR, 3.01, 95% CI, 1.06-9.16, P = .04). Early and late prenatal CRP mediated 96% and 86% of the association between maternal prepregnancy body mass index and offspring asthma, respectively. CONCLUSIONS: Higher prenatal CRP and an increase in CRP from early to late pregnancy are associated with childhood asthma. Systemic inflammation during pregnancy associated with modifiable maternal characteristics may be an important determinant of childhood asthma risk.

The composition of the gut microbiota in early childhood is linked to asthma risk but the role of the gut microbiota in older patients with established asthma is less clear. Here, we used a cohort of 38 school-aged children (19 with asthma) and 57 adults (17 with asthma) to develop a model that aids in the design of mechanistic experiments in gnotobiotic mice. These experiments show that enterotoxigenic Bacteroides fragilis (ETBF) is associated with increased gut permeability, oxidative stress, and markers of Th17-mediated inflammation in the lungs of mice following ovalbumin sensitization and challenge (OSC). Further, ETBF is enriched in a human population with asthma compared to healthy controls. Our results provide evidence that ETBF has the potential to alter the phenotype of airway inflammation in a subset of patients with asthma outside of early childhood which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.

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.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.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.Overall, our results suggest that the early-life, including prenatal, fecal microbiome modifies risk of asthma, especially asthma with onset by age 3 years.

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

Allergy/immunology specialists in the US prescribing allergy immunotherapy (AIT) have placed a heavy value on practical experience and anecdotal evidence rather than research-based evidence. With the extensive research on AIT conducted in the last few decades, the time has come to better implement evidence-based medicine (EBM) for AIT. The goal of this review was to critically assess EBM for debated concepts in US AIT practice for respiratory allergies in the context and quality of today's regulatory standards. Debated topics reviewed were the efficacy and safety of AIT in various subgroups (e.g., polyallergic patients, older patients, patients with asthma, pregnant women), diagnosis topics (e.g., skin prick test vs allergen-specific serum IgE, factors affecting skin prick tests, use of nasal or conjunctival allergen challenges, and telemedicine for diagnosis), and dosing topics (e.g., optimal dosing for subcutaneous immunotherapy and sublingual immunotherapy tablets, US liquid allergen extract history, duration of treatment, biomarkers of efficacy). In addition, EBM for patient-centered AIT issues (e.g., adherence, use of practice guidelines, pharmacoeconomics) and the approach to implementation of AIT EBM in future clinical practice was also addressed. The EBM for each concept was briefly summarized, and when possible, a practical, concise recommendation was given.

BackgroundDNA methylation of cytosines at CpG dinucleotides is a widespread epigenetic mark; but genome-wide variation has been relatively unexplored due to the limited representation of variable CpGs on commercial high-throughput arrays.ObjectiveTo explore this hidden portion of the epigenome, we combined whole-genome bisulfite sequencing (WGBS) with in silico evidence of gene regulatory regions to design a custom array of high-value CpGs. We focused these studies in airway epithelial cells from children with and without allergic asthma because these cells mediate the effects of inhaled microbes, pollution, and allergens on asthma and allergic disease risk.MethodsWe identified differentially methylated regions (DMRs) from WGBS in nasal epithelial cell (NEC) DNA from 39 children with and without allergic asthma of both European and African ancestries. We selected CpGs from DMRs, previous allergy or asthma Epigenome-Wide Association Studies (EWAS), or Genome-Wide Association Study (GWAS) loci, and overlapped them with functional annotations for inclusion on a custom Asthma&Allergy array. Using both the Custom and EPIC arrays, we performed EWAS of allergic sensitization (AS) in NEC DNA from children in the URECA birth cohort and using the Custom array in the INSPIRE birth cohort. We assigned each CpG on the arrays to its nearest gene and its promotor capture Hi-C interacting gene and performed expression quantitative trait methylation (eQTM) studies for both sets of genes.ResultsCustom array CpGs were enriched for intermediate methylation (IM) levels compared to EPIC CpGs. IM CpGs were further enriched among those associated with AS and for eQTMs on both arrays.ConclusionsOur study revealed signature features of high-value CpGs and evidence for epigenetic regulation of genes at AS EWAS loci that are robust to race/ethnicity, ascertainment, age, and geography.Clinical ImplicationsThese studies identified allergic sensitization-associated differentially methylated CpGs and their target genes in airway epithelium, providing potential epigenetic mechanisms in the development of allergic diseases and suggesting novel drug targets.Capsule SummaryThis study of previously unexplored regions of the airway epithelial methylome revealed novel epigenetic mechanisms regulating genes previously implicated in the pathogenesis of asthma and allergic diseases.

Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone.This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588.Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab.Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations.US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete.We sought to determine phenotypic factors associated with FEVLung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEVA total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEVIn children with severe and nonsevere asthma, several clinically relevant factors predict FEV

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p