Researchers uncover diverse asthma endotypes in youths using nasal transcriptomics

Study highlights the prevalence of T2-low and T17-high asthma endotypes among racially and ethnically minoritized youths, paving the way for precision medicine approaches.

Study: Transcriptomic Profiles in Nasal EpitheliumandAsthmaEndotypes in Youth. Image Credit: New Africa/Shutterstock.com

In a recent study published in the JAMA, a group of researchers identified asthma endotypes in youths aged 6 to 20 years by analyzing transcriptomic profiles in nasal epithelium and their association with clinical and immunological characteristics.

Background

Asthma, the most common chronic respiratory illness in children, disproportionately affects racially and ethnically minoritized groups in the United States, with Puerto Rican and non-Hispanic Black youths experiencing higher rates of emergency department visits compared to non-Hispanic White youths.

While T helper 2 (T2)-high asthma, characterized by eosinophilic inflammation and elevated levels of interleukin (IL)-4, IL-5, and IL-13, has been extensively studied and treated with targeted therapies, less is known about T2-low endotypes, including T17-high asthma and paucigranulocytic asthma.

These non-T2-high endotypes are poorly understood, particularly in underserved youth populations. Further research is essential to clarify their molecular mechanisms and improve diagnostic and therapeutic approaches.

About the studies

The study leverages data from three key investigations to analyze asthma endotypes in diverse youth populations using nasal RNA profiles.

• Stress and Treatment Response in Puerto Rican and African American Children with Asthma (STAR):

Conducted between 2018 and 2022, this study examined six-week responses to inhaled corticosteroids (ICS) in youths aged 8-20 years from Puerto Rico and Pittsburgh. Participants met criteria including physician-diagnosed mild-to-moderate persistent asthma, at least three Puerto Rican or African American grandparents, no recent corticosteroid use or upper respiratory infections (URIs), and no significant smoking history. They provided demographic and respiratory health data, underwent spirometry and blood testing (IgE and eosinophil counts), and nasal RNA sequencing prior to ICS treatment.

• Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR):

This study, conducted from 2014 to 2017, focused on Puerto Rican youths aged 9-20 years with asthma. Participants underwent spirometry, blood tests, and nasal sampling for gene expression analysis, using methods similar to STAR.

• Vitamin D Kids Asthma (VDKA):

Conducted from 2016 to 2019, this 48-week randomized trial investigated the effects of vitamin D3 supplementation in children aged 6-16 years with severe asthma. An ancillary component included nasal sampling for transcriptomic analysis.

All three studies received ethical approval and contributed data on nasal RNA profiles, enabling the identification of T2 and T17 asthma endotypes across diverse populations of children and adolescents.

Study results

This analysis examined 459 participants with asthma from three studies: STAR (n = 156), EVA-PR (n = 237), and VDKA (n = 66), with demographic and clinical characteristics varying across cohorts. EVA-PR included exclusively Puerto Rican participants, while STAR and VDKA primarily involved African American or non-Hispanic Black participants.

The mean age differed, with VDKA participants being the youngest (10.3 years), followed by STAR (14.2 years) and EVA-PR (15.4 years). Overweight or obesity was prevalent, affecting between 45.6% and 65.4% of participants, and most individuals had Medicaid or medical assistance, with 1% to 4% uninsured.

K-means clustering of nasal transcriptomic profiles identified three asthma endotypes consistently across cohorts: T2-high (22.7%–29.1%), T17-high (35.0%–47.0%), and T2-low/T17-low (30.3%–37.8%). T2-high participants exhibited higher levels of total IgE, eosinophils, and allergen sensitization compared to T2-low profiles, although 50% to 73.3% of T2-low participants also displayed allergen-specific IgE positivity.

Clinical findings varied across cohorts. In STAR, T2-high participants were more likely to have allergic rhinitis, higher household incomes, and asthma-related emergency visits. T17-high participants were generally younger, while obesity was associated with T2-low profiles in STAR and EVA-PR but linked to T2-high profiles in VDKA. Lung function measures did not significantly differ between endotypes.

Biomarker analysis in STAR established cutoff values for identifying T2-high profiles: total IgE (≥417.5 IU/mL), eosinophils (≥210.4 cells/μL), and FeNO (≥32.5 parts per billion). A decision tree model integrating these biomarkers enhanced predictive accuracy.

Differential gene expression analysis identified 3,516 genes associated with T2-high profiles, highlighting IL-13 signaling and 2,494 genes for T17-high profiles, emphasizing cytokine and interferon-γ pathways. Key genes included FPR1, TREM1, and IL23A, while gene coexpression networks provided further insights into molecular mechanisms unique to each endotype.

This comprehensive analysis demonstrates the clinical and molecular diversity of asthma endotypes and underscores the value of personalized approaches in asthma treatment and management.

Conclusions

This study found that T2-low asthma endotypes, including T17-high and T2-low/T17-low profiles, were more common than T2-high asthma among racially and ethnically minoritized youths.

Detailed profiling showed that single biomarkers, such as IgE and eosinophils, were not highly accurate for identifying T2-high asthma. However, a decision tree model using IgE (≥418 IU/mL) and FeNO (≥28 ppb) improved prediction accuracy.

Unlike earlier research, this analysis excluded participants with recent corticosteroid use, reducing confounding factors. Nasal transcriptomic analysis revealed novel therapeutic targets for T17-high asthma, including FPR1, TREM1, and IL23A. These findings suggest the potential for endotype-specific treatments, advancing precision medicine in asthma care.