Asthma Management Program Research Articles

Consistent Multi-Omic Relationships Uncover Molecular Basis of Pediatric Asthma IgE Regulation.

Serum total immunoglobulin E levels (total IgE) capture the state of the immune system in relation to allergic sensitization. High levels are associated with airway obstruction and poor clinical outcomes in pediatric asthma. Inconsistent patient response to anti-IgE therapies motivates discovery of molecular mechanisms underlying serum IgE level differences in children with asthma. To uncover these mechanisms using complementary metabolomic and transcriptomic data, abundance levels of 529 named metabolites and expression levels of 22,772 genes were measured among children with asthma in the Childhood Asthma Management Program (CAMP, N=564) and the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS, N=309) via the TOPMed initiative. Gene-metabolite associations dependent on IgE were identified within each cohort using multivariate linear models and were interpreted in a biochemical context using network topology, pathway and chemical enrichment, and representation within reactions. A total of 1,617 total IgE-dependent gene-metabolite associations from GACRS and 29,885 from CAMP met significance cutoffs. Of these, glycine and guanidinoacetic acid (GAA) were associated with the most genes in both cohorts, and the associations represented reactions central to glycine, serine, and threonine metabolism and arginine and proline metabolism. Pathway and chemical enrichment analysis further highlighted additional related pathways of interest. The results of this study suggest that GAA may modulate total IgE levels in two independent pediatric asthma cohorts with different characteristics, supporting the use of L-Arginine as a potential therapeutic for asthma exacerbation. Other potentially new targetable pathways are also uncovered.

Circulating miRNAs associate with historical childhood asthma hospitalization in different serum vitamin D groups

BackgroundVitamin D may help to alleviate asthma exacerbation because of its anti-inflammation effect, but the evidence is inconsistent in childhood asthma. MiRNAs are important mediators in asthma pathogenesis and also excellent non-invasive biomarkers. We hypothesized that circulating miRNAs are associated with asthma exacerbation and modified by vitamin D levels.MethodsWe sequenced baseline serum miRNAs from 461 participants in the Childhood Asthma Management Program (CAMP). Logistic regression was used to associate miRNA expression with asthma exacerbation through interaction analysis first and then stratified by vitamin D insufficient and sufficient groups. Microarray from lymphoblastoid B-cells (LCLs) treated by vitamin D or sham of 43 subjects in CAMP were used for validation in vitro. The function of miRNAs was associated with gene modules by weighted gene co-expression network analysis (WGCNA).ResultsWe identified eleven miRNAs associated with asthma exacerbation with vitamin D effect modification. Of which, five were significant in vitamin D insufficient group and nine were significant in vitamin D sufficient group. Six miRNAs, including hsa-miR-143-3p, hsa-miR-192-5p, hsa-miR-151a-5p, hsa-miR-24-3p, hsa-miR-22-3p and hsa-miR-451a were significantly associated with gene modules of immune-related functions, implying miRNAs may mediate vitamin D effect on asthma exacerbation through immune pathways. In addition, hsa-miR-143-3p and hsa-miR-451a are potential predictors of childhood asthma exacerbation at different vitamin D levels.ConclusionsmiRNAs are potential mediators of asthma exacerbation and their effects are directly impacted by vitamin D levels.

Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma

Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n=660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n=1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value=0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value=2.6×10-5), SLC8A1 (P-value=3.9×10-5); and TENM4 (P-value=4.9×10-5). This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

Risk factors contributing to Pennsylvania childhood asthma

Childhood asthma continues to present a significant clinical and economic challenge in the U.S. Implementing more proactive treatment and comprehensive asthma management programs is imperative to addressing this national financial and health burden. Understanding the importance of various risk factors in asthma hospitalization and diagnosis rates can aid in earlier identification, treatment, and prevention of asthma altogether. In this study, we hypothesized that population density was the greatest predictor of childhood asthma hospitalization rate and diagnosis rate. We examined a total of 18 demographic, socioeconomic, and environmental risk factors at Pennsylvania’s county level to identify the risk factors contributing to childhood asthma hospitalization and diagnosis rate. Using a multiple linear regression model, we found “population density” and “percentage of Hispanic population” to be most strongly correlated with both childhood asthma hospitalization rate and diagnosis rates. In addition, “tobacco retail density”, “number of high ozone days”, and “childhood lead poisoning rate” were important factors associated with asthma hospitalization rate, while “percentage of population living in a rural area” was associated with asthma diagnosis rate. Our study provides a greater understanding of the influence of certain demographic and environmental exposures on Pennsylvania’s childhood asthma and emphasizes the importance of prevention.

A novel piwi-interacting RNA associates with type 2–high asthma phenotypes

Piwi-interacting RNAs (piRNAs), comprising the largest noncoding RNA group, regulate transcriptional processes. Whether piRNAs are associated with type 2 (T2)-high asthma is unknown. We sought to investigate the association between piRNAs and T2-high asthma in childhood asthma. We sequenced plasma samples from 462 subjects in the Childhood Asthma Management Program (CAMP) as the discovery cohort and 1165 subjects in the Genetics of Asthma in Costa Rica Study (GACRS) as a replication cohort. Sequencing reads were filtered first, and piRNA reads were annotated and normalized. Linear regression was used for the association analysis of piRNAs and peripheral blood eosinophil count, total serum IgE level, and long-term asthma exacerbation in children with asthma. Mediation analysis was performed to investigate the effect direction. We then ascertained if the circulating piRNAs were present in asthmatic airway epithelial cells in a Gene Expression Omnibus (GEO; www.ncbi.nlm.nih.gov/geo) public data set. Fifteen piRNAs were significantly associated with eosinophil count in CAMP (P≤ .05), and 3 were successfully replicated in GACRS. Eleven piRNAs were associated with total IgE in CAMP, and one of these was replicated in GACRS. All 22 significant piRNAs were identified in epithelial cells invitro, and 6 of these were differentially expressed between subjects with asthma and healthy controls. Fourteen piRNAs were associated with long-term asthma exacerbation, and effect of piRNAs on long-term asthma exacerbation are mediated through eosinophil count and serum IgE level. piRNAs are associated with peripheral blood eosinophils and total serum IgE in childhood asthma and may play important roles in T2-high asthma.

Factors associated with poor health-related quality of life among patients with asthma: A hospital-based study from Jordan

<b>Purpose</b>: Exploring the factors that are associated with diminished health-related quality of life (HRQOL) in patients with asthma is essential to reach the optimal HRQOL. This study aim to assess HRQOL and its associated factors in patients with asthma in Jordan.<br /> <b>Methods</b>: This cross-sectional study was conducted on patients with asthma attending King Abdullah University Hospital and Jordan University Hospital in Jordan. In addition to socio-demographic variables, the study survey included mini asthma quality of life questionnaire (mini AQLQ) to measure HRQOL and asthma control test (ACT) to assess the degree of asthma control in asthmatic patients. Binary logistic regression was used to build a model of the independent predictors of poor HRQOL in the study participants.<br /> <b>Results</b>: Of the 314 participating patients, 70.1% were females, with a mean age of 51.47±16.37 years. 61.1% of the participants had low HRQOL, with a total mean mini AQLQ score of 4.30±1.30. Results revealed that advanced age (OR=0.961; 95% CI: 0.936-0.986; p<0.05) and lack of daily exercise (OR=0.233; 95% CI: 0.085-0.637; p<0.01) were significant predictors of poor HRQOL in patients with asthma, while better controlled disease, manifested by higher ACT score was associated with better HRQOL in these patients (OR=1.499; 95% CI: 1.344-1.672; p<0.01).<br /> <b>Conclusions</b>: HRQOL represents an area for improvement in patients with asthma. The current study provides insight on the factors associated with poor HRQOL. Future interventions and asthma management programs should focus on improving asthma control and encouraging physical activity, particularly for older patients, with the aim of improving HRQOL among patients with asthma.

Effects of Obesity and Depression on the Incidence of Asthma in Korean Older Adults: A Secondary Analysis of the Korea National Health and Nutrition Examination Survey 2020

Purpose: This study investigated the effects of body mass index (BMI), waist circumference (WC), and depression on asthma in older adults Koreans.Methods: Data for 1,388 individuals (≥65 years) were extracted from the Korea National Health and Nutrition Examination Survey (KNHANES Ⅷ-2, 2020). Complex sampling design data were analyzed using stratification, clustering, and weights. Data were analyzed using unweighted frequencies, weighted percentages, estimated means and standard errors, the Rao-Scott x<sup>2</sup> test, and multiple logistic regression analysis, which was performed to identify variables that influenced asthma after adjusting for confounding factors.Results: The factors influencing asthma in the older adults were a depression diagnosis, age at the onset of depression, current depression status, and gender. In contrast, BMI and WC did not affect asthma. A diagnosis of depression had an odds ratio of 3.07 for asthma in the older adults. Furthermore, the odds ratios for asthma in the older adults were 5.08 for depression onset at <49 years and 3.37 for current depression compared to no depression diagnosis. The odds ratio for asthma in female older adults was 1.35.Conclusion: The results of this study suggest that asthma in the older adults could be detected early through depression symptoms. This study also provides evidence that depression-related interventions should be included in asthma prevention and management programs for the older adults in Korea.

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n=3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n=674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n=787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P<7.94E-04) that can be explored as potential therapeutic targets. By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels. US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.

Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features. We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRSAsthma) and spirometry (FEV1 and FEV1/forced vital capacity; PRSspiro) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO). We developed and tested 2 asthma PRSs and applied the higher performing PRSAsthma and a previously published PRSspiro to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry. In meta-analyses of 102,477 participants, the PRSAsthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRSspiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRSspiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRSspiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRSAsthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRSspiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRSAsthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRSspiro was associated with asthma exacerbations in White, LatinX, and East Asian participants. PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts.

Systems Genomics Reveals microRNA Regulation of ICS Response in Childhood Asthma.

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. The purpose of this study was to identify key associations between circulating miRNAs and ICS response in childhood asthma. 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. 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. 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.

Implementation of a primary care asthma management quality improvement programme across 68 general practice sites

Despite national and international guidelines, asthma is frequently misdiagnosed, control is poor and unnecessary deaths are far too common. Large scale asthma management programme such as that undertaken in Finland, can improve asthma outcomes. A primary care asthma management quality improvement programme was developed with the support of the British Lung Foundation (now Asthma + Lung UK) and Optimum Patient Care (OPC) Limited. It was delivered and cascaded to all relevant staff at participating practices in three Clinical Commissioning Groups. The programme focussed on improving diagnostic accuracy, management of risk and control, patient self-management and overall asthma control. Patient data were extracted by OPC for the 12 months before (baseline) and after (outcome) the intervention. In the three CCGs, 68 GP practices participated in the programme. Uptake from practices was higher in the CCG that included asthma in its incentivised quality improvement programme. Asthma outcome data were successfully extracted from 64 practices caring for 673,593 patients. Primary outcome (Royal College of Physicians Three Questions [RCP3Q]) data were available in both the baseline and outcome periods for 10,328 patients in whom good asthma control (RCP3Q = 0) increased from 36.0% to 39.2% (p < 0.001) after the intervention. The odds ratio of reporting good asthma control following the intervention was 1.15 (95% CI 1.09–1.22), p < 0.0001. This asthma management programme produced modest but highly statistically significant improvements in asthma outcomes. Key lessons learnt from this small-scale implementation will enable the methodology to be improved to maximise benefit in a larger scale role out.

Asthma Symptom Action Plan (ASAP): Assessing the Need for, Creating and Implementing a Standardized Form for San Diego County Schools

Asthma is one of the most common chronic medical conditions affecting school-aged children. One in two children report school absences due to asthma per year. SAMPRO (School-based Asthma, Allergy & Anaphylaxis Management Program) endorses standardized asthma action plans (AAP) in schools.

Transcriptome-wide association study of circulating IgE levels identifies novel targets for asthma and allergic diseases.

Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study across 17,873 mRNA gene-level transcripts. We identified 216 significant transcripts at a false discovery rate <0.05. We conducted replication using the meta-analysis of two independent external studies: the Childhood Asthma Management Program (n=610) and the Genetic Epidemiology of Asthma in Costa Rica Study (n=326); we then reversed the discovery and replication cohorts, which revealed 59 significant genes that replicated in both directions. Gene ontology analysis revealed that many of these genes were implicated in immune function pathways, including defense response, inflammatory response, and cytokine production. Mendelian randomization (MR) analysis revealed four genes (CLC, CCDC21, S100A13, and GCNT1) as putatively causal (p<0.05) regulators of IgE levels. GCNT1 (beta=1.5, p=0.01)-which is a top result in the MR analysis of expression in relation to asthma and allergic diseases-plays a role in regulating T helper type 1 cell homing, lymphocyte trafficking, and B cell differentiation. Our findings build upon prior knowledge of IgE regulation and provide a deeper understanding of underlying molecular mechanisms. The IgE-associated genes that we identified-particularly those implicated in MR analysis-can be explored as promising therapeutic targets for asthma and IgE-related diseases.

Asthma in Disaster Zones

The Global Asthma Network (GAN) report issued in 2022 and the Global Initiative for Asthma (GINA) report of 2023 emphasize challenges and difficulties faced by health workers in managing asthma in Low- and Middle-income countries (LMICs). Among the many reasons for these difficulties are insufficient knowledge of health workers of management guidelines, and lack of medical resources especially inhaler medications1,2,3. When available in limited amounts, these resources are prohibitively expensive4,5,6. These reports did not address the impact of disaster on asthma care. In this article, we aim to highlight this issue, hoping that future international asthma reports will take this aspect into consideration. When disasters such as war and earthquakes occur in LMIC, several aspects of asthma care are negatively impacted. First, challenges in asthma management are compounded by difficulties related to displacement, overcrowding in shelters, immigration of health care workers (HCW), damage to health facilities, limited referral capacity to specialists, and limited availability of expensive inhalers4,5,6. Second, governments face logistical challenges. While the immediate need may be to provide emergency needs,6,7 health facilities should secure medications to provide care according to World Health Organization (WHO) guidelines7. Third, asthma research and data collection are hampered.8 Digital health could be a solution9,10. It is therefore imperative that we develop suitable asthma management programs applicable to zones in turmoil4,11,12. We conducted a literature search on challenges in asthma management in zones of turmoil. We used the following search keywords and phrases: asthma and war, asthma and turmoil, asthma and earthquakes, and asthma and disasters. We reviewed all publications that relate to this topic that appeared in the literature between 2014 and 2023. Based on this review and analysis, we list several lessons learned, conclusions and recommendations.

Factors Associated With Persistence of Severe Asthma From Late Adolescence to Early Adulthood

To determine risk factors in childhood that predict severe persistent asthma in late adolescence and early adulthood.Patients aged 5 to 12 years with mild to moderate asthma and a positive methacholine challenge enrolled in the Childhood Asthma Management Program (CAMP) trial.The CAMP participants above who had data available from late adolescence to early adulthood were included. The first study visit at age 18 years was used to determine asthma activity in late adolescence, whereas the first study at age 22 years was used to determine asthma activity in early adulthood. The American Thoracic Society definition of severe asthma was used for patients on high dose inhaled corticosteroids and the National Asthma Education and Prevention Program Expert Panel Report (NAEPP EPR) 3 definition of severe asthma was used for those not receiving high dose inhaled corticosteroids. Additional criteria for intermittent and persistent asthma were included. The following factors were analyzed: secondhand smoke exposure, maternal smoking during pregnancy, body mass index percentile, hay fever, eczema, food allergy, parental asthma being sensitized and exposed to any perennial aeroallergen, bronchial hyperreactivity, prebronchodilator FEV1/FVC ratio, post bronchodilator FEV1/FVC ratio, bronchial hyperresponsiveness to methacholine challenge, log10 of serum total IgE and log10 of serum absolute eosinophil count. Characteristics were compared from baseline to late adolescence and from baseline to early adulthood.Six hundred eighty-two CAMP participants were included. Of these participants, severe asthma was present in 81 (12%) participants in late adolescence and 131 (19%) participants in early adulthood. Half of the patients with severe asthma in late adolescence continued to have severe asthma into early adulthood. About 18% of patients improved severity, 61% did not change, and 21% of patients worsened in severity from late adolescence to early adulthood. The postbronchodilator percent predicted FEV1 and pre and post bronchodilator FEV1/FVC ratio significantly decreased from childhood to late adolescence and from late adolescence to early adulthood (P < .0001), whereas prebronchodilator FEV1 values increased from childhood to late adolescence (P < .0001) and stabilized in early adulthood (P = .040). Bronchodilator reversibility and bronchial hyperresponsiveness each decreased from childhood to late adolescence (P < .0001), whereas bronchial hyperresponsiveness also significantly decreased from childhood to early adulthood (P = .0003). Patients with persistent and severe asthma had higher serum IgE in late adolescence and were more likely to have a positive aeroallergen skin test, along with sensitization and exposure to perennial allergens in childhood. Significant factors in early childhood that were associated with persistence of severe asthma from late adolescence to early adulthood included a younger age, male sex, no reported hay fever, a low prebronchodilator FEV1/FVC ratio, a low postbronchodilator FEV1/FVC ratio, and a physician diagnosis of moderate asthma during the screening period. Notably, for every 5% decrease in post bronchodilator FEV1/FVC ratio in childhood, the odds of severe asthma persistence increased by 2.36-fold (P < .0001) as well as maternal smoking during pregnancy increased odds of severe asthma persistence by 3.17-fold (P = .020). There was a strong association between a reduced-growth lung function trajectory and severe asthma persistence.Lower FEV1/FVC ratio in childhood and maternal smoking during pregnancy were the strongest predictors for severe asthma between late adolescence and early adulthood.Understanding early factors for persistence of asthma into adulthood can help develop targeted primary prevention measures such as reduction of smoking during pregnancy as well as early intervention measures with therapies to preserve lung function in childhood.URL: www.pediatrics.org/cgi/doi/10.1542/peds.10.1164/rccm.202010-3763OC

FGF20 and PGM2 variants are associated with childhood asthma in family-based whole-genome sequencing studies.

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. 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. 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. 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.

Implementation of a pediatric asthma management program in rural primary care clinics

Objective Rural communities experience a significant asthma burden. We pilot tested the implementation of Easy Breathing, a decision support program for improving primary care provider adherence to asthma guidelines in a rural community, and characterized asthma risk factors for enrollees. Methods We implemented Easy Breathing in two rural primary care practices for two years. Patient demographics, exposure histories, asthma severity, asthma medications, and treatment plans were collected. Providers’ adherence to guidelines included the frequency of children with persistent asthma who were prescribed guidelines-based therapy and the frequency of children with a written asthma treatment plan on file. Clinicians provided feedback on the feasibility and acceptability of Easy Breathing using a validated survey tool and through semi-structured interviews. Results Two providers implemented the program. Enrollment included 518 children, of whom 135 (26%) had physician-confirmed asthma. After enrollment into Easy Breathing, 75% of children with asthma received a written asthma treatment plan All children with persistent asthma were prescribed an anti-inflammatory drug as part of their treatment plan. Providers (n = 2) rated Easy breathing as highly acceptable (M = 4.5), feasible (M = 4.5), and appropriate (M = 4.5). Qualitative feedback was positive, with suggestions to integrate the paper-based program into the electronic health record system for broader uptake. Enrollees with asthma were more likely to have a family history of asthma and endorse exposure to tobacco smoke and cockroaches. Conclusions Easy Breathing shows promise as a decision support system that can be implemented in rural, medically underserved communities via primary care.

Zinc finger protein 33B demonstrates sex interaction with atopy-related markers in childhood asthma.

Sex differences related to immune responses can influence atopic manifestations in childhood asthma. While genome-wide association studies have investigated a sex-specific genetic architecture of the immune response, gene-by-sex interactions have not been extensively analysed for atopy-related markers including allergy skin tests, IgE and eosinophils in asthmatic children. We performed a genome-wide gene-by-sex interaction analysis for atopy-related markers using whole-genome sequencing data based on 889 trios from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) and 284 trios from the Childhood Asthma Management Program (CAMP). We also tested the findings in UK Biobank participants with self-reported childhood asthma. Furthermore, downstream analyses in GACRS integrated gene expression to disentangle observed associations. Single nucleotide polymorphism (SNP) rs1255383 at 10q11.21 demonstrated a genome-wide significant gene-by-sex interaction (pinteraction=9.08×10-10) for atopy (positive skin test) with opposite direction of effects between females and males. In the UK Biobank participants with a history of childhood asthma, the signal was consistently observed with the same sex-specific effect directions for high eosinophil count (pinteraction=0.0058). Gene expression of ZNF33B (zinc finger protein 33B), located at 10q11.21, was moderately associated with atopy in girls, but not in boys. We report SNPs in/near a zinc finger gene as novel sex-differential loci for atopy-related markers with opposite effect directions in females and males. A potential role for ZNF33B should be studied further as an important driver of sex-divergent features of atopy in childhood asthma.

Genome-wide association study in minority children with asthma implicates DNAH5 in bronchodilator responsiveness

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 < 0.05). No genetic variant was associated with BDR at the genome-wide significant threshold in Mexicans and African Americans. Our findings help inform genetic underpinnings of BDR for understudied minority patients with asthma, but the limited availability of genetic data for racial/ethnic minority children with asthma remains a paramount challenge.

Sparse group variable selection for gene-environment interactions in the longitudinal study.

Penalized variable selection for high-dimensional longitudinal data has received much attention as it can account for the correlation among repeated measurements while providing additional and essential information for improved identification and prediction performance. Despite the success, in longitudinal studies, the potential of penalization methods is far from fully understood for accommodating structured sparsity. In this article, we develop a sparse group penalization method to conduct the bi-level gene-environment (G E) interaction study under the repeatedly measured phenotype. Within the quadratic inference function framework, the proposed method can achieve simultaneous identification of main and interaction effects on both the group and individual levels. Simulation studies have shown that the proposed method outperforms major competitors. In the case study of asthma data from the Childhood Asthma Management Program, we conduct G E study by using high-dimensional single nucleotide polymorphism data as genetic factors and the longitudinal trait, forced expiratory volume in 1 s, as the phenotype. Our method leads to improved prediction and identification of main and interaction effects with important implications.