Background: Childhood-onset asthma is highly heritable, with nearly 200 risk loci identified in genome-wide association studies. Aggregated polygenic risk scores (PRSs) can be used to quantify genetic predisposition to asthma, but their power to predict asthma severity in multiancestral groups has not been previously evaluated. Objective: Our aim was to examine the predictive power of biobank-derived asthma PRSs in 4 multiancestry asthma study cohorts of children living in US urban environments. Methods: We generated PRSs for asthma, derived from a large-scale genome-wide association meta-analysis, and assessed genetic predictions across different subphenotypes of asthma and tested for associations between genetic asthma risk and measures of asthma severity. Results: PRS prediction was significantly stronger for more symptomatic asthma phenotypes (P < .001), and scores were significantly higher in difficult-to-control versus easy-to-control asthma (P = .02). Genetic risk was also significantly associated with more frequent exacerbations (P = .03), higher blood eosinophil levels (P = .01), and lower lung function (P < .001). Conclusion: Cumulative genetic risk for asthma is associated with disease severity and exacerbation risk in children with asthma.

Importance:While biologic therapies targeting type 2 (T2) inflammation reduce acute exacerbation rates in children with asthma and T2 inflammation, exacerbations still occur, and the underlying molecular mechanisms are poorly defined. Objective:To identify multiple distinct molecular mechanisms implicated in asthma exacerbations by characterizing respiratory illnesses among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab vs placebo. Design, Setting, and Participants:This is a secondary analysis of the Mechanisms Underlying Asthma Exacerbations Prevented and Persistent With Immune-Based Therapy: A Systems Approach Phase 2 (MUPPITS-2) double-blind, placebo-controlled, parallel-group, randomized clinical trial comparing treatment with mepolizumab vs placebo among children with exacerbation-prone asthma in low-income urban centers in 9 US cities. Data analysis was performed from September 2022 to April 2025. Intervention:Participants were randomized to receive either mepolizumab (aged 6-11 years: 40 mg; aged 12-17 years: 100 mg) or matching placebo by subcutaneous injection once every 4 weeks for 52 weeks. Main Outcomes and Measures:The primary measurement was a transcriptomic modular analysis by RNA sequencing of nasal samples obtained during acute respiratory illnesses. Associations among upper airway transcriptional signatures, the clinical outcome of respiratory illnesses, and pulmonary functions were investigated. Results:Of the 290 participants enrolled in the MUPPITS-2 trial, 108 participants (median [IQR] age, 10.0 [9.0-13.0] years; 48 [44%] female) were sampled during 176 acute respiratory illness events. During illness events resulting in asthma exacerbations, children receiving mepolizumab demonstrated decreased expression of an eosinophil-associated module associated with T2 inflammation (log2 fold change [FC] estimate, -0.60; false discovery rate [FDR] < .05) but increased expression of gene modules associated with epithelial and macrophage inflammatory pathways relative to children receiving placebo (log2 FC estimates, 0.22-0.85; FDR < .05). Both groups showed higher expression of mucus secretion and cellular stress response pathways during exacerbations relative to nonexacerbation illnesses. The mepolizumab group demonstrated upregulation of epithelial inflammatory pathways in exacerbations irrespective of a respiratory virus, while macrophage pathways contributed specifically to viral exacerbations. Three distinct, semiorthogonal inflammatory axes were shown to underlie the majority of the heterogeneity among exacerbations in the 2 groups. Conclusions and Relevance:The study's findings implicate multiple alternative inflammatory pathways associated with the epithelium and macrophages, as well as mucus hypersecretion, as mechanisms of residual acute exacerbations in children receiving mepolizumab. Further, they indicate that multiple distinct inflammatory axes can independently contribute to asthma exacerbations. Trial Registration:ClinicalTrials.gov Identifier: NCT03292588.

Mepolizumab (anti-IL5 therapy) reduces asthma exacerbations in urban children with exacerbation-prone eosinophilic asthma. We previously utilized nasal transcriptomics to identify inflammatory pathways (gene co-expression modules) associated with asthma exacerbations despite this therapy. In this study, we applied differential gene correlation analysis on these targeted gene co-expression modules to gain better insight into the treatment effects on correlation structure within gene networks. Mepolizumab treatment resulted in loss of correlation amongst eosinophil-specific genes but conservation and even strengthening of correlation amongst mast cell-specific genes, T2 cytokines, and airway epithelial inflammatory genes. Notably, mepolizumab induced significant gain in correlation of genes associated with multiple aspects of airway epithelial inflammation including those related to extracellular matrix production and nitric oxide synthesis, and this change was associated with a poor clinical response to mepolizumab. These findings highlight that using differential gene correlation analysis offers insight into the molecular regulatory effects of treatment on gene interactions and may lead to better understanding of disease mechanisms and therapeutic responses. ClinicalTrials.gov ID: NCT03292588.

Background: Peanut is a major cause of food allergy. HLA genes have been consistently associated with peanut allergy in association studies. To date, however, there have been very few genetic studies of peanut allergy in non-Hispanic Black (Black) individuals, a group disproportionately affected by food allergy. Objective: Our aim was to study the relationship between HLA alleles and peanut allergy among Black individuals. Methods: The analysis consisted of Black participants from the Study of Asthma-Related Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE), a large cohort of individuals from metropolitan Detroit. At the time of enrollment, participants provided detailed food allergy histories, including symptoms. Four-digit resolution HLA allele calls were made using whole genome sequence data. Results: The cases consisted of 119 individuals with reported peanut allergy and 59 individuals with peanut-related anaphylaxis; the comparison group consisted of 2640 individuals without reported food allergy. HLA-DRB1∗13:02 was the most significant allele associated with peanut allergy (adjusted odds ratio = 1.94 [95% CI = 1.28-2.93]), and HLA-DQA1∗01:02 was the top association with peanut-related anaphylaxis (aOR = 1.67 [95% CI = 1.14-2.44]). Amino acid polymorphisms at position 71 in the binding groove of HLA-DRB1 were associated with peanut allergy and estimated to affect peanut allergen binding affinity. Conclusions: In a cohort of Black individuals, this study independently identified the same associations of peanut allergy and HLA that were previously observed in non-Hispanic White individuals. Our findings suggest that specific HLA binding groove amino acid polymorphisms may confer similar peanut allergy risk across population groups and HLA alleles.

While biologic therapies targeting type 2 (T2) inflammation reduce acute exacerbation rates in children with asthma and T2 inflammation, exacerbations still occur, and the underlying molecular mechanisms are poorly defined. To identify multiple distinct molecular mechanisms implicated in asthma exacerbations by characterizing respiratory illnesses among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab vs placebo. This is a secondary analysis of the Mechanisms Underlying Asthma Exacerbations Prevented and Persistent With Immune-Based Therapy: A Systems Approach Phase 2 (MUPPITS-2) double-blind, placebo-controlled, parallel-group, randomized clinical trial comparing treatment with mepolizumab vs placebo among children with exacerbation-prone asthma in low-income urban centers in 9 US cities. Data analysis was performed from September 2022 to April 2025. Participants were randomized to receive either mepolizumab (aged 6-11 years: 40 mg; aged 12-17 years: 100 mg) or matching placebo by subcutaneous injection once every 4 weeks for 52 weeks. The primary measurement was a transcriptomic modular analysis by RNA sequencing of nasal samples obtained during acute respiratory illnesses. Associations among upper airway transcriptional signatures, the clinical outcome of respiratory illnesses, and pulmonary functions were investigated. Of the 290 participants enrolled in the MUPPITS-2 trial, 108 participants (median [IQR] age, 10.0 [9.0-13.0] years; 48 [44%] female) were sampled during 176 acute respiratory illness events. During illness events resulting in asthma exacerbations, children receiving mepolizumab demonstrated decreased expression of an eosinophil-associated module associated with T2 inflammation (log2 fold change [FC] estimate, −0.60; false discovery rate [FDR] < .05) but increased expression of gene modules associated with epithelial and macrophage inflammatory pathways relative to children receiving placebo (log2 FC estimates, 0.22-0.85; FDR < .05). Both groups showed higher expression of mucus secretion and cellular stress response pathways during exacerbations relative to nonexacerbation illnesses. The mepolizumab group demonstrated upregulation of epithelial inflammatory pathways in exacerbations irrespective of a respiratory virus, while macrophage pathways contributed specifically to viral exacerbations. Three distinct, semiorthogonal inflammatory axes were shown to underlie the majority of the heterogeneity among exacerbations in the 2 groups. The study’s findings implicate multiple alternative inflammatory pathways associated with the epithelium and macrophages, as well as mucus hypersecretion, as mechanisms of residual acute exacerbations in children receiving mepolizumab. Further, they indicate that multiple distinct inflammatory axes can independently contribute to asthma exacerbations. ClinicalTrials.gov Identifier: NCT03292588

Background:Earlier studies have demonstrated significant differences in food allergy by race and ethnicity, particularly for seafood and shrimp. Shrimp allergy is particularly interesting given the potential for cross-reactive sensitization from other arthropods. Objectives:We characterized risk factors for shrimp allergy and shrimp sensitization. Methods:Data from electronic health records were abstracted for food allergies among patients who sought care at a large health system between October 1, 2010, and April 1, 2024. Geocoded addresses were linked to US Census data to identify characteristics associated with shrimp allergy. Non-Hispanic Black participants from the Study of Asthma-Related Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) were assessed for allergic sensitization using an IgE array, and survey data collected from participants were evaluated for association with shrimp, cockroach, and dust mite sensitization. Results:Among 2,975,183 health system patients, 4,709 individuals reported shrimp allergy. Compared to White individuals, rates of shrimp allergy were significantly higher in Black, Asian/Pacific Islander, Native American, and Latino individuals. Shrimp allergy was higher with increasing age, female sex, and asthma, and it was inversely related to median household income. Among SAPPHIRE participants, sensitization to shrimp, cockroach, and dust mite was positively associated with total IgE levels and proportion of African ancestry, but inversely associated with head of household level of education. Conclusions:Both shrimp allergy and sensitization were associated with sociodemographic factors, suggesting that environmental exposures leading to cross-reactive sensitization may be important risk factors. Nevertheless, sensitization was also associated with ancestry, highlighting the potential importance of group-specific genetic risk factors.

Rationale: Systemic corticosteroids are standard-of-care treatment for asthma exacerbations; however, little is known about whether corticosteroid effects on airway inflammatory pathways differ when added to biologic therapies targeting type 2 inflammation. Methods: 290 urban children (6-17 years) with exacerbation-prone eosinophilic asthma were randomized (1:1) to q4 week placebo or mepolizumab injections added to guideline-based care for 52 weeks. Nasal lavage samples were collected at baseline (before treatment), post-exacerbation (5-10 days after starting systemic corticosteroids), and on treatment for RNA-sequencing. Differentially expressed genes (DEGs) were assessed using mixed effects modeling (significance threshold FDR<0.05). Results: 98 participants were evaluated following 170 exacerbation events (placebo:105, mepolizumab:65). In the placebo group, there were no significant differentially expressed genes comparing on treatment to before treatment timepoints. In the placebo group, there were 6363 significant DEGs (2734 increased, 3629 decreased) comparing post-exacerbation to on treatment. In the mepolizumab group, there were 1404 significant DEGs (664 increased, 740 decreased) comparing on treatment to before treatment (Fig1A: x-axis). In the mepolizumab group, there were 1111 significant DEGs (413 increased, 698 decreased) comparing post-exacerbation to on treatment (Figure 1A: y-axis). In the post-exacerbation versus on treatment contrasts, there were 885 overlapping significant DEGs (348 increased, 537 decreased) between the placebo and mepolizumab participants. Mepolizumab reduced expression of eosinophil-associated genes (CCL23, GATA1, CLC, PRSS33, PTGDR2, ADORA3, THBS4) on treatment, with a larger decrease post-corticosteroid (more reduced than placebo) (FDR<0.05) (Fig1B). Mepolizumab did not significantly alter expression of mast cell/T2 cytokine-related genes (HDC, CPA3, GATA2, TPSAB2, IL5, IL13, IL1RL1, ALOX15) on treatment; however, expression of these genes significantly decreased post-corticosteroid (more reduced than placebo) (FDR<0.05) (Fig1B). Mepolizumab increased expression of genes associated with epithelial and airway inflammation (CFTR, ERBB2, BMP3, TRPV4) on treatment; however, expression of these genes returned to baseline levels post-corticosteroid (FDR<0.05) (Fig1B). Conclusions: By comparing differential gene expression across treatment groups and time points, we identified overlapping DEGs related to systemic corticosteroid effects, DEGs related only to mepolizumab treatment, and clusters of functionally related genes with additive effects of mepolizumab plus systemic corticosteroids. Mepolizumab enhances the actions of oral corticosteroids on eosinophil related pathways in relation to exacerbations. Oral corticosteroids provide the added benefit of down-regulating mast cell and T2 cytokine pathways. Finally, oral corticosteroids reverse the up-regulation of epithelial inflammatory pathways that occurred during mepolizumab treatment.

Background:Childhood-onset asthma is highly heritable, with nearly 200 risk loci identified in genome-wide association studies. Aggregated polygenic risk scores can be used to quantify genetic predisposition to asthma, but their power to predict asthma severity in multi-ancestral groups has not been determined. Objective:Our aim was to examine the predictive power of biobank-derived asthma polygenic risk scores in children with asthma living in urban environments. Methods:We generated polygenic risk scores for asthma, derived from a large-scale genome-wide association meta-analysis, in four multi-ancestry asthma study cohorts of children living in urban environments. We assessed genetic predictions across different subphenotypes of asthma and tested for associations between genetic asthma risk and measures of asthma severity. Results:Genetic asthma prediction was significantly stronger for more symptomatic asthma phenotypes (P<0.001). Polygenic risk scores were significantly higher in difficult-to-control vs. easy-to-control asthma (P=0.02). Genetic risk was also significantly associated with more frequent exacerbations (P=0.03), higher blood eosinophil levels (P=0.01), and lower lung function (P<0.001). Conclusion:Cumulative genetic risk for asthma is associated with disease severity and exacerbation risk in children with asthma living in urban environments.

Peanut is a major cause of food allergy. HLA genes have been consistently associated with peanut allergy in association studies. To date, however, there have been very few genetic studies of peanut allergy in non-Hispanic Black (Black) individuals, a group disproportionately affected by food allergy. Our aim was to study the relationship between HLA alleles and peanut allergy among Black individuals. The analysis consisted of Black participants from the Study of Asthma-Related Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE), a large cohort of individuals from metropolitan Detroit. At the time of enrollment, participants provided detailed food allergy histories, including symptoms. Four-digit resolution HLA allele calls were made using whole genome sequence data. The cases consisted of 119 individuals with reported peanut allergy and 59 individuals with peanut-related anaphylaxis; the comparison group consisted of 2640 individuals without reported food allergy. HLA-DRB1∗13:02 was the most significant allele associated with peanut allergy (adjusted odds ratio = 1.94 [95% CI = 1.28-2.93]), and HLA-DQA1∗01:02 was the top association with peanut-related anaphylaxis (aOR = 1.67 [95% CI = 1.14-2.44]). Amino acid polymorphisms at position 71 in the binding groove of HLA-DRB1 were associated with peanut allergy and estimated to affect peanut allergen binding affinity. In a cohort of Black individuals, this study independently identified the same associations of peanut allergy and HLA that were previously observed in non-Hispanic White individuals. Our findings suggest that specific HLA binding groove amino acid polymorphisms may confer similar peanut allergy risk across population groups and HLA alleles.

RATIONALE: 4G4G/4G5G SERPINE1 genotypes produce high concentrations of plasminogen activator inhibitor-1 and are associated with worse asthma outcomes. A secondary analysis of the American Lung Association (ALA) SOYA trial showed that soy isoflavones significantly reduced asthma exacerbations versus placebo among patients with 4G4G/4G5G SERPINE1 genotypes. We hypothesized that baseline characteristics predict optimal responders to soy isoflavones among this subgroup. METHODS: ALA-SOYA was a randomized controlled trial that tested the efficacy of soy isoflavones vs. placebo for reducing asthma exacerbations among adolescents and adults with symptomatic asthma. In this responder analysis among participants with 4G4G/4G5G SERPINE1 genotypes, baseline demographic and clinical characteristics were tested for effect modification of the treatment assignment (soy/placebo) on the primary outcome of annualized number of asthma exacerbations using interaction terms in negative binomial regression models, with a significance threshold of p-interaction=0.15. RESULTS: Data were available for n=168 participants. Soy reduced the annualized number of asthma exacerbations relative to placebo among patients with 4G4G/4G5G SERPINE1 genotypes (incident rate ratio (IRR)=0.37, 95% confidence interval (CI): 0.15-0.90, p=0.028). Self-reported adherence to baseline controller therapy was the only significant effect modifier of this association (interaction p=0.115), with those using inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) controller therapy at least twice weekly experiencing reductions in asthma exacerbations with soy versus placebo (IRR = 0.25, 95% CI: 0.09-0.69; p= 0.007) but not among those using ICS/LABA controller therapy less frequently (IRR = 1.33, 95% CI: 0.22-8.02; p= 0.757). CONCLUSION: Soy isoflavones reduce asthma exacerbations among patients with the 4G4G/4G5G SERPINE1 genotypes and are most effective in those with greater adherence to asthma controller therapy regimens.