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Background Asthma is a heterogeneous common respiratory disease that remains poorly understood. The established genetic associations fail to explain the high estimated heritability, and the prevalence of asthma differs between populations and geographic regions. Robust association analyses incorporating different genetic ancestries and whole-genome sequencing data may identify novel genetic associations. Methods We performed family-based genome-wide association analyses of childhood-onset asthma based on whole-genome sequencing (WGS) data for the ‘The Genetic Epidemiology of Asthma in Costa Rica’ study (GACRS) and the Childhood Asthma Management Program (CAMP). Based on parent–child trios with children diagnosed with asthma, we performed a single variant analysis using an additive and a recessive genetic model and a region-based association analysis of low-frequency and rare variants. Results Based on 1180 asthmatic trios (894 GACRS trios and 286 CAMP trios, a total of 3540 samples with WGS data), we identified three novel genetic loci associated with childhood-onset asthma: rs4832738 on 4p14 ($P=1.72\ast{10}^{-9}$, recessive model), rs1581479 on 8p22 ($P=1.47\ast{10}^{-8}$, additive model) and rs73367537 on 10q26 ($P=1.21\ast{10}^{-8}$, additive model in GACRS only). Integrative analyses suggested potential novel candidate genes underlying these associations: PGM2 on 4p14 and FGF20 on 8p22. Conclusion Our family-based whole-genome sequencing analysis identified three novel genetic loci for childhood-onset asthma. Gene expression data and integrative analyses point to PGM2 on 4p14 and FGF20 on 8p22 as linked genes. Furthermore, region-based analyses suggest independent potential low-frequency/rare variant associations on 8p22. Follow-up analyses are needed to understand the functional mechanisms and generalizability of these associations.

RATIONALE: Outdoor air pollution causes emergency department visits and hospitalizations for childhood asthma. In the United States, the Air Quality Index (AQI) alerts the public to air quality and provides behavioral recommendations to reduce exposure and harm, yet little is known about the relationship between the AQI and childhood asthma exacerbations. OBJECTIVES: To test for association between the AQI and childhood asthma exacerbations resulting in emergency department visits and hospitalizations. METHODS: This was a retrospective time-stratified case-crossover study, conducted using medical records data from 2010 through 2018 for children aged 6–17 years with a primary diagnosis of an asthma exacerbation (defined as an emergency department visit or hospitalization for asthma) at UPMC Children’s Hospital of Pittsburgh. Daily AQI data was obtained for Allegheny County, Pennsylvania from the Environmental Protection Agency. Conditional logistic regression was used for analyses of the AQI (as both a continuous and categorical variable) and asthma exacerbations. Stratified analyses were conducted to explore modification of the AQI effects on asthma exacerbations by race and other covariates. RESULTS: There were 6,573 events. Particulate matter

In the United States, the coronavirus disease-2019 (COVID-19) pandemic has disproportionally affected Black, Latinx, and Indigenous populations, immigrants, and economically disadvantaged individuals. Such historically marginalized groups are more often employed in low-wage jobs without health insurance and have higher rates of infection, hospitalization, and death from COVID-19 than non-Latinx White individuals. Mistrust in the health care system, language barriers, and limited health literacy have hindered vaccination rates in minorities, further exacerbating health disparities rooted in structural, institutional, and socioeconomic inequities. In this article, we discuss the lessons learned over the last 2years and how to mitigate health disparities moving forward.

Background: Asthmatic patients’ responses to inhaled corticosteroids (ICS) are variable and difficult to quantify. We have previously defined a Cross-sectional Asthma STEroid Response (CASTER) measure of ICS response. MicroRNAs (miRNAs) have shown strong effects on asthma and inflammatory processes. Objective: The purpose of this study was to identify key associations between circulating miRNAs and ICS response in childhood asthma. Methods: Small RNA sequencing in peripheral blood serum from 580 children with asthma on ICS treatment from The Genetics of Asthma in Costa Rica Study (GACRS) was used to identify miRNAs associated with ICS response using generalized linear models. Replication was conducted in children on ICS from the Childhood Asthma Management Program (CAMP) cohort. The association between replicated miRNAs and the transcriptome of lymphoblastoid cell lines in response to a glucocorticoid was assessed. Results: The association study on the GACRS cohort identified 36 miRNAs associated with ICS response at 10% false discovery rate (FDR), three of which (miR-28-5p, miR-339-3p, and miR-432-5p) were in the same direction of effect and significant in the CAMP replication cohort. In addition, in vitro steroid response lymphoblastoid gene expression analysis revealed 22 dexamethasone responsive genes were significantly associated with three replicated miRNAs. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) revealed a significant association between miR-339-3p and two modules (black and magenta) of genes associated with immune response and inflammation pathways. Conclusion: This study highlighted significant association between circulating miRNAs miR-28-5p, miR-339-3p, and miR-432-5p and ICS response. miR-339-3p may be involved in immune dysregulation, which leads to a poor response to ICS treatment.

RATIONALE: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). OBJECTIVES: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. METHODS: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. MEASUREMENTS AND MAIN RESULTS: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10(−5)) and postbronchodilator (p-ANOVA = 1.8 × 10(−5)) FEV(1)/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. CONCLUSIONS: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.

Asthma affects a large number of people living in the Americas, a vast and diverse geographic region comprising 35 nations in the Caribbean and North, Central, and South America. The marked variability in the prevalence, morbidity, and mortality from asthma across and within nations in the Americas offers a unique opportunity to improve our understanding of the risk factors and management of asthma phenotypes and endotypes in children and adults. Moreover, a better assessment of the causes and treatment of asthma in less economically developed regions in the Americas would help diagnose and treat individuals migrating from those areas to Canada and the United States. In this focused review, we first assess the epidemiology of asthma, review known and potential risk factors, and examine commonalities and differences in asthma management across the Americas. We then discuss future directions in research and health policies to improve the prevention, diagnosis, and management of pediatric and adult asthma in the Americas, including standardized and periodic assessment of asthma burden across the region; large-scale longitudinal studies including omics and comprehensive environmental data on racially and ethnically diverse populations; and dissemination and implementation of guidelines for asthma management across the spectrum of disease severity. New initiatives should recognize differences in socioeconomic development and health care systems across the region while paying particular attention to novel or more impactful risk factors for asthma in the Americas, including indoor pollutants such as biomass fuel, tobacco use, infectious agents and the microbiome, and psychosocial stressor and chronic stress.

BackgroundThe current United States asthma management guidelines recommend usage of the Air Quality Index (AQI) for outdoor activity modification when air pollution is high. Little is known about parental knowledge and usage of air quality including the AQI in managing childhood asthma.MethodsForty parents (or legal guardians) of children with persistent asthma completed a questionnaire designed to assess 4 areas related to outdoor air pollution: awareness, perception, behavioral modification, and prior healthcare provider discussion. Descriptive statistics were obtained and Fisher's exact test was used for analysis of behavioral change by selected variables.ResultsAlmost all parents reported awareness of air quality alerts or AQI, however, only 20% checked the AQI on the AirNow app or website. Most parents reported air pollution as a trigger (65%), yet few parents reported behavioral modification of their child's outdoor activity based on the perception of poor air quality (43%) or based on AQI or alerts (40%). Over half of parents reported a healthcare provider had ever discussed air pollution as a trigger, with few parents (23%) reporting recommendations for behavior change. Perception of air pollution as a trigger, healthcare provider discussion and recommendations, and usage of AirNow were associated with increased reported activity change.ConclusionHealthcare providers should discuss outdoor air pollution during asthma management in children and should discuss AirNow as a source for AQI information and behavioral recommendations.

Bronchiolitis is a leading cause of infant hospitalizations but its immunopathology remains poorly understood. Here we present data from 244 infants hospitalized with bronchiolitis in a multicenter prospective study, assessing the host response (transcriptome), microbial composition, and microbial function (metatranscriptome) in the nasopharyngeal airway, and associate them with disease severity. We investigate individual associations with disease severity identify host response, microbial taxonomical, and microbial functional modules by network analyses. We also determine the integrated relationship of these modules with severity. Several modules are significantly associated with risks of positive pressure ventilation use, including the host-type I interferon, neutrophil/interleukin-1, T cell regulation, microbial-branched-chain amino acid metabolism, and nicotinamide adenine dinucleotide hydrogen modules. Taken together, we show complex interplays between host and microbiome, and their contribution to disease severity.

Motivation Allele-specific differences in molecular traits can be obtained from next-generation sequencing data and could potentially improve testing power, but such information is usually overlooked in association studies. Furthermore, the variation of molecular quantitative traits (e.g. gene expression) could result from the interaction effect of genotypes and phenotypes, but it is challenging to identify such interaction signals in complex disease studies in humans due to small genetic effect sizes and/or small sample sizes. Results We develop a novel statistical method, the combined haplotype interaction test (CHIT), which tests for association between molecular quantitative traits and phenotype–genotype interactions by modeling the total read counts and allele-specific reads in a target region. CHIT can be used as a supplementary analysis to the regular linear interaction regression. In our simulations, CHIT obtains non-inflated type I error rates, and it has higher power than a standard interaction quantitative trait locus approach based on linear regression models. Finally, we illustrate CHIT by testing associations between gene expression obtained by RNA-seq and the interaction of SNPs and atopy status from a study of childhood asthma in Puerto Ricans, and results demonstrate that CHIT could be more powerful than a standard linear interaction expression quantitative trait loci approach. Availability and implementation The CHIT algorithm has been implemented in Python. The source code and documentation are available and can be downloaded from https://github.com/QiYanPitt/CHIT. Supplementary information Supplementary data are available at Bioinformatics online.

Variability in response to short-acting β2-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10–8) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P

Most genome-wide association studies of obesity and body mass index (BMI) have so far assumed an additive mode of inheritance in their analysis, although association testing supports a recessive effect for some of the established loci, for example, rs1421085 in FTO. In two whole-genome sequencing (WGS) studies of children with asthma and their parents (892 Costa Rican trios and 286 North American trios), we discovered an association between a locus (rs9292139) in LOC102724122 and BMI that reaches genome-wide significance under a recessive model in the combined analysis. As the association does not achieve significance under an additive model, our finding illustrates the benefits of the recessive model in WGS analyses.

Background Little is known about the genetic determinants of severe asthma exacerbations. Objectives We aimed to identify genetic variants associated with asthma hospitalizations. Methods We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses. Results At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10–8); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10–6. In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of .01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2, HLA-DRB6, and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue. Conclusions We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data–based mendelian randomization analyses.

International audience; Background: Allergic diseases often occur in combination (multimorbidity). Human blood transcriptome studies have not addressed multimorbidity. Large-scale gene expression data were combined to retrieve biomarkers and signaling pathways to disentangle allergic multimorbidity phenotypes. Methods: Integrated transcriptomic analysis was conducted in 1233 participants with a discovery phase using gene expression data (Human Transcriptome Array 2.0) from whole blood of 786 children from three European birth cohorts (MeDALL), and a replication phase using RNA Sequencing data from an independent cohort (EVA-PR, n = 447). Allergic diseases (asthma, atopic dermatitis, rhinitis) were considered as single disease or multimorbidity (at least two diseases), and compared with no disease. Results: Fifty genes were differentially expressed in allergic diseases. Thirty-two were not previously described in allergy. Eight genes were consistently overexpressed in all types of multimorbidity for asthma, dermatitis, and rhinitis (CLC, EMR4P, IL5RA, FRRS1, HRH4, SLC29A1, SIGLEC8, IL1RL1). All genes were replicated the in EVA-PR cohort. RT-qPCR validated the overexpression of selected genes. In MeDALL, 27 genes were differentially expressed in rhinitis alone, but none was significant for asthma or dermatitis alone. The multimorbidity signature was enriched in eosinophil-associated immune response and signal transduction. Protein-protein interaction network analysis identified IL5/JAK/STAT and IL33/ST2/IRAK/TRAF as key signaling pathways in multimorbid diseases. Synergistic effect of multimorbidity on gene expression levels was found. Conclusion: A signature of eight genes identifies multimorbidity for asthma, rhinitis, and dermatitis. Our results have clinical and mechanistic implications, and suggest that multimorbidity should be considered differently than allergic diseases occurring alone.

Background Occupational exposures at the WTC site after 11 September 2001 have been associated with presumably inflammatory chronic lower airway diseases. Aims In this study, we describe the trajectories of expiratory air flow decline, identify subgroups with adverse progression, and investigate the association of those trajectories with quantitative computed tomography (QCT) imaging measurement of increased and decreased lung density. Methods We examined the trajectories of expiratory air flow decline in a group of 1,321 former WTC workers and volunteers with at least three periodic spirometries, and using QCT‐measured low (LAV%, −950 HU) and high (HAV%, from −600 to −250 HU) attenuation volume percent. We calculated the individual regression line slopes for first‐second forced expiratory volume (FEV1slope), identified subjects with rapidly declining (“accelerated decliners”) and increasing (“improved”), and compared them to subjects with “intermediate” (0 to −66.5 mL/year) FEV1slope. We then used multinomial logistic regression to model those three trajectories, and the two lung attenuation metrics. Results The mean longitudinal FEV1 slopes for the entire study population, and its intermediate, decliner, and improved subgroups were, respectively, −40.4, −34.3, −106.5, and 37.6 mL/year. In unadjusted and adjusted analyses, LAV% and HAV% were both associated with “accelerated decliner” status (ORadj, 95% CI 2.37, 1.41–3.97, and 1.77, 1.08–2.89, respectively), compared to the intermediate decline. Conclusions Longitudinal FEV1 decline in this cohort, known to be associated with QCT proximal airway inflammation metric, is also associated with QCT indicators of increased and decreased lung density. The improved FEV1 trajectory did not seem to be associated with lung density metrics.

BACKGROUND: The mechanisms underlying the known link between overweight/obesity and childhood asthma are unclear. We aimed to identify differentially expressed genes and pathways associated with obesity-related asthma through a transcriptomic analysis of nasal airway epithelium. METHODS: We compared the whole transcriptome in nasal airway epithelium of youth with overweight or obesity and asthma with that of youth of normal weight and asthma, using RNA sequencing data from a cohort of 235 Puerto Ricans aged 9 to 20 years (EVA-PR) and an independent cohort of 66 children aged 6 to 16 years in Pittsburgh (VDKA). Differential expression analysis adjusting for age, sex, sequencing plate number, sample sorting protocol, and the first five principal components was performed independently in each cohort. Results from the two cohorts were combined in a transcriptome-wide meta-analysis. Gene enrichment and network analyses were performed on top genes. RESULTS: In the meta-analysis, 29 genes were associated with obesity-related asthma at an FDR-adjusted P

Variable number of tandem repeats (VNTRs) are major source of genetic variation in human. However due to their repetitive nature and large size, it is challenging to genotype them by short-read sequencing. Therefore, there is limited understanding of how they contribute to complex traits such as cystic fibrosis (CF) lung function. Genome-wide association study (GWAS) of CF lung disease identified two independent signals near SLC9A3 displaying a high density of VNTRs and CpG islands. Here, we used long-read (PacBio) phased sequence (N=58) to identify the boundaries and lengths of 49 common (frequency >2%) VNTRs in the region. Subsequently, associations of the VNTRs with gene expression were investigated in CF nasal epithelia using RNA sequencing (N=46). Two VNTRs tagged by the two GWAS signals and overlapping CpG islands were independently associated with SLC9A3 expression in CF nasal epithelia. The two VNTRs together explained 24% of SLC9A3 gene expression variation. One of them was also associated with TPPP expression. We then showed that the VNTR lengths can be estimated with good accuracy in short-read sequence in a subset of individuals with data on both long (PacBio) and short-read (10X Genomics) technologies (N=52). VNTR lengths were then estimated in the Genotype-Tissue Expression project (GTEx) and their association with gene expression was investigated. Both VNTRs were associated with SLC9A3 expression in multiple non-CF GTEx tissues including lung. The results confirm that VNTRs can explain substantial variation in gene expression and be responsible for GWAS signals, and highlight the critical role of long-read sequencing.

BACKGROUND: Poor diet quality may contribute to the disproportionate asthma burden in Puerto Rican youth. OBJECTIVE: To examine whether an unhealthy diet at one or two study visits conducted over ~5 years is associated with asthma, severe asthma exacerbations, and worse lung function in Puerto Rican youth. METHODS: Prospective study of 406 Puerto Rican youth aged 6–14 years at a baseline visit and 9–20 years at a follow-up visit. As in prior work, diet was assessed using a dietary score ranging from −2 to +2. Our exposure of interest was an unhealthy diet, defined as a non-positive dietary score (0 to −2) at one or both visits. Our outcomes of interest were asthma (defined as physician-diagnosed asthma and ≥1 episode of wheeze in the year prior to the second visit), ≥1 severe asthma exacerbation in the year prior to the second visit, and change in percent predicted lung function measures (FEV(1), FVC, and FEV(1)/FVC) between the first and second visits. RESULTS: In a multivariable analysis, an unhealthy diet at both visits was associated with increased odds of asthma (adjusted odds ratio [aOR]=3.38, 95% confidence interval [CI]=1.74 to 6.57) and severe asthma exacerbations (aOR=2.65, 95% CI=1.16 to 6.03), but not with change in lung function. CONCLUSIONS: An unhealthy diet at both visits was associated with increased odds of asthma and severe asthma exacerbations compared with a healthy diet at both visits. Our findings support health policies promoting a healthy diet in Puerto Rican youth, a population at high risk for asthma.

In a transcription-wide association study of nasal epithelium, we identify novel and previously reported susceptibility genes for atopic asthma in children and show that gene co-expression networks differ markedly between children with and without atopic asthma.

Latinos are heavily affected with childhood asthma. Little is known about epigenetic mechanisms of asthma in Latino youth. We conducted a meta-analysis of two epigenome-wide association studies (EWAS) of asthma, using DNA from white blood cells (WBCs) from 1,136 Latino children and youth aged 6 to 20 years. Genes near the top CpG sites in this EWAS were examined in a pathway enrichment analysis, and we then assessed whether our results replicated those from publicly available data from three independent EWAS conducted in non-Latino populations. We found that DNA methylation profiles differed between subjects with and without asthma. After adjustment for covariates and multiple testing, two CpGs were differentially methylated at a false discovery rate (FDR)-adjusted P

BACKGROUND Little is known about the risk factors for atopic and nonatopic asthma among children in Puerto Rico. We aimed to identify modifiable risk factors for atopic and nonatopic asthma in this vulnerable population. METHODS Case-control study of children with (n = 305) and without (n = 327) asthma in San Juan (Puerto Rico). Asthma was defined as physician-diagnosed asthma and wheeze in the previous year. Atopic asthma (n = 210) was defined as asthma and greater than or equal to one positive IgE to aero-allergens. Nonatopic asthma (n = 95) was defined as asthma and no positive IgE to the allergens tested. Logistic regression was used for the multivariable analysis of atopic and nonatopic asthma. RESULTS In a multivariable analysis, body mass index (BMI) z score, prematurity, parental asthma, lifetime exposure to gun violence, and having a bird in the child's home were associated with increased odds of atopic asthma, while each one-point increment in a dietary score (range: -2 [least healthy diet] to +2 [healthiest diet]) was associated with 37% reduced odds of atopic asthma (95% confidence interval [CI] = 0.48-0.81; P

Over the last two decades, a growing body of evidence has linked chronic psychosocial stress to asthma. Exposure to violence can lead to chronic stress and has received recent attention in the asthma literature, as is a common exposure for people living in urban settings, particularly in the U.S. Improving our understanding of whether and how exposure to chronic stressors causes or worsens asthma could help us gain insights into disease pathogenesis, design public health policies, and develop new interventions. In this essay, the evidence linking violence or stress to asthma is explored, including recent insights on potential mechanisms, and a discussion on current challenges and future directions. To date, experimental and observational studies support a causal association between chronic stress and worse asthma control, and increasing evidence suggests that pre- or post-natal chronic stress may lead to new-onset asthma. Such evidence supports conducting randomized controlled trials of stress-reduction interventions to improve asthma control in subjects with high chronic stress. On the other hand, more experimental and longitudinal studies are needed to better understand if violence exposure leads to asthma or worse asthma outcomes. Longitudinal studies with assessment of co-exposures and coping mechanisms are key to not only better understand the independent effects of violence or stress on asthma but also to identify factors that could ameliorate or worsen such effects.

Rationale: Women have a higher burden of asthma than men. Although sex hormones may explain sex differences in asthma, their role is unclear. Objectives: To examine sex hormone levels and asthma in adults. Methods: Cross-sectional study of serum levels of free testosterone and estradiol and current asthma in 7,615 adults (3,953 men and 3,662 women) aged 18–79 years who participated in the 2013–2014 and 2015–2016 U.S. National Health and Nutrition Examination Survey. Logistic regression was used for the multivariable analysis of sex hormones and current asthma, which was conducted separately in women and men. Measurements and Main Results: Free testosterone levels in the fourth quartile were associated with lower odds of current asthma in women (odds ratio [OR] for the fourth quartile [Q4] vs. Q1, 0.56; 95% confidence interval [CI], 0.39–0.80). Given an interaction between obesity and sex hormones on current asthma, we stratified the analysis by obesity. In this analysis, elevated free testosterone (OR for Q4 vs. Q1, 0.59; 95% CI, 0.37–0.91) and estradiol (OR for Q4 vs. Q1, 0.43; 95% CI, 0.23–0.78) levels were associated with reduced odds of current asthma in obese women, and an elevated serum estradiol was associated with lower odds of current asthma in nonobese men (OR for Q4 vs. Q1, 0.44; 95% CI, 0.21–0.90). Conclusions: Our findings suggest that sex hormones play a role in known sex differences in asthma in adults. Moreover, our results suggest that obesity modifies the effects of sex hormones on asthma in adults.

MicroRNAs have been independently associated with asthma and COPD; however, it is unclear if microRNA associations will overlap when evaluating retrospective acute exacerbations. Objective: We hypothesized that peripheral blood microRNAs would be associated with retrospective acute asthma exacerbations in a pediatric asthma cohort and that such associations may also be relevant to acute COPD exacerbations. Methods: We conducted small-RNA sequencing on 374 whole-blood samples from children with asthma ages 6–14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS) and 450 current and former adult smokers with and without COPD who participated in the COPDGene study. Measurements and Main Results: After QC, we had 351 samples and 649 microRNAs for Differential Expression (DE) analysis between the frequent (n = 183) and no or infrequent exacerbation (n = 168) groups in GACRS. Fifteen upregulated miRs had odds ratios (OR) between 1.22 and 1.59 for a doubling of miR counts, while five downregulated miRs had ORs between 0.57 and 0.8. These were assessed for generalization in COPDGene, where three of the upregulated miRs (miR-532-3p, miR-296-5p, and miR-766-3p) and two of the downregulated miRs (miR-7-5p and miR-451b) replicated. Pathway enrichment analysis showed MAPK and PI3K-Akt signaling pathways were strongly enriched for target genes of DE miRNAs and miRNAs generalizing to COPD exacerbations, as well as infection response pathways to various pathogens. Conclusion: miRs (451b; 7-5p; 532-3p; 296-5p and 766-3p) associated with both childhood asthma and adult COPD exacerbations may play a vital role in airflow obstruction and exacerbations and point to shared genomic regulatory machinery underlying exacerbations in both diseases.

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value

BACKGROUND: Children with severe asthma have substantial morbidity and healthcare utilization. Pediatric severe asthma is a heterogeneous disease, and a multidisciplinary approach can improve the diagnosis and management of these children. METHODS: We reviewed the electronic health records for patients seen in the Severe Asthma Clinic (SAC) at UPMC Children’s Hospital of Pittsburgh between August 2012 and October 2019. RESULTS: Of the 110 patients in whom we extracted data, 46% were female, 48% were Black/African American, and 41% had ≥1 admission to the pediatric intensive care unit (PICU) for asthma. Compared to patients without a PICU admission, those with ≥1 PICU admission were more likely to be non-White (64.4% vs 41.5%, P=0.031) and more atopic (eosinophil count geometric mean= 673 vs 319 cells/mm(3), P=0.002; total IgE geometric mean=754 vs 303 KU/L, P=0.003), and to have lower pre-bronchodilator FEV1 (58.6% [±18.1%] vs 69.9% [±18.7%], P=0.002) and elevated FeNO (60% vs 22%, P=0.02). In this cohort, 84% of patients were prescribed high-dose ICS/LABA and 36% were on biologics. Following enrollment in the SAC, severe exacerbations decreased from 3.2/year to 2.2/year (P

OBJECTIVE: Coffee intake has been inversely associated with asthma in adults. We examined the relation between urinary levels of caffeine or caffeine metabolites and asthma, lung function, and fractional exhaled nitric oxide (FeNO) in adults. METHODS: Cross-sectional study of 2,832 adults aged 18-79 years in the US National Health and Nutrition Examination Survey (NHANES). Multivariable logistic or linear regression was used for the analysis of urinary levels of caffeine or each of its three major metabolites (paraxanthine, theobromine, and theophylline) and current asthma, lung function, and FeNO. RESULTS: Subjects with urinary paraxanthine levels in the fourth quartile (Q4) had 53% lower odds of current asthma than those whose urinary paraxanthine levels were in the first quartile (Q1; 95% confidence = 0.22 to 1.00). Among never and former smokers, subjects with urinary theophylline levels above Q1 had 49% lower odds of current asthma than those whose urinary theophylline level was in Q1 (95% CI = 0.31 to 0.85). Among subjects without current asthma, each log(10)-unit increment in paraxanthine level was associated with a 0.83% increment in percent predicted (%pred) FEV(1) and a 1.27% increment in %pred FVC, while each log(10)-unit in theophylline was associated with a 1.24% increment in %pred FVC. Neither urinary caffeine nor any urinary caffeine metabolite was associated with bronchodilator response or FeNO. CONCLUSIONS: Our findings suggest that two caffeine metabolites (theophylline and paraxanthine) may contribute to the previously reported inverse association between coffee intake and asthma in adults.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

Type 2 T helper (TH2) cells are protective against parasitic worm infections but also aggravate allergic inflammation. Although the role of dendritic cells (DCs) in TH2 cell differentiation is well...

Type 2 T helper (T(H)2) cells are protective against parasitic worm infections but also aggravate allergic inflammation. Although the role of dendritic cells (DCs) in T(H)2 cell differentiation is well established, the underlying mechanisms are largely unknown. Here, we show that DC induction of T(H)2 cells depends on membrane-associated RING-CH-1 (MARCH1) ubiquitin ligase. The pro-T(H)2 effect of MARCH1 relied on lymph node (LN)–resident DCs, which triggered T cell receptor (TCR) signaling and induced GATA-3 expression from naïve CD4(+) T cells independent of tissue-driven migratory DCs. Mice with mutations in the ubiquitin acceptor sites of MHCII and CD86, the two substrates of MARCH1, failed to develop T(H)2 cells. These findings suggest that T(H)2 cell development depends on ubiquitin-mediated clearance of antigen-presenting and costimulatory molecules by LN-resident DCs and consequent control of TCR signaling.

Background Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma. Methods Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci. Results Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci. Conclusions This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.

Importance Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3supplementation reduces severe childhood asthma exacerbations is unclear. Objective To determine whether vitamin D3supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old). Main Outcomes and Measures The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3group vs 253 days in the placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85];P = .63). Vitamin D3supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3group, n = 11; placebo group, n = 9). Conclusions and Relevance Among children with persistent asthma and low vitamin D levels, vitamin D3supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration ClinicalTrials.gov Identifier:NCT02687815

Introduction: Reports and associations of COPD and ACO with WTC occupational exposures have been inconsistent. Using spirometric case definitions, we examined that association in the largest WTC occupational surveillance cohort. Methods: We tested for association between ACO and COPD and early arrival (within 48 hr, when dust and fumes exposures were more intense) at the 2001 WTC disaster site in workers with at least two spirometries between 2002 and 2018. Case definitions of COPD required fixed obstruction, and, for ACO pre-bronchodilator obstruction with >400 ml FEV1 response to bronchodilator. We used a nested 1:4 case-control design matching on sex and height (within 5 cm) using density sampling. We imputed missing data. Results: The study population consisted of 17,996 former WTC workers, predominantly (85.4%) male and overweight or obese (85.6%), of whom 586 (3.3%) and 258 (1.4%) cases met the COPD and ACO case definition, respectively. In adjusted analyses, COPD and ACO were associated with early arrival at the WTC site, with adjusted odds ratio, and 95% confidence interval of 1.3, 1.03-1.64, and 1.66, 1.1-2.49, respectively, independently from covariates such as smoking, age, cohort entry period, metabolic syndrome indicators, and high peripheral eosinophil count, among others. Discussion: In this cohort of WTC workers, spirometrically defined COPD and ACO were both associated with WTC exposure intensity. With substantially lower prevalence and effect sizes, we confirmed the findings from another cohort where the case definitions were based on self-reported physician diagnoses (PMID 32930623).

Background: Well-designed clinical research needs to obtain information that is applicable to the general population. However, most current studies fail to include substantial cohorts of racial/ethnic minority populations. Such underrepresentation may lead to delayed diagnosis or misdiagnosis of disease, wide application of approved interventions without appropriate knowledge of their usefulness in certain populations, and development of recommendations that are not broadly applicable. Goals: To develop best practices for recruitment and retention of racial/ethnic minorities for clinical research in pulmonary, critical care, and sleep medicine. Methods: The American Thoracic Society convened a workshop in May of 2019. This included an international interprofessional group from academia, industry, the NIH, and the U.S. Food and Drug Administration, with expertise ranging from clinical and biomedical research to community-based participatory research methods and patient advocacy. Workshop participants addressed historical and current mistrust of scientific research, systemic bias, and social and structural barriers to minority participation in clinical research. A literature search of PubMed and Google Scholar was performed to support conclusions. The search was not a systematic review of the literature. Results: Barriers at the individual, interpersonal, institutional, and federal/policy levels were identified as limiting to minority participation in clinical research. Through the use of a multilevel framework, workshop participants proposed evidence-based solutions to the identified barriers. Conclusions: To date, minority participation in clinical research is not representative of the U.S. and global populations. This American Thoracic Society research statement identifies potential evidence-based solutions by applying a multilevel framework that is anchored in community engagement methods and patient advocacy.