Nasal sampling reveals three asthma endotypes among minoritized youth

Key takeaways:

• Transcriptomic profiles included T2^HIGH, T17^HIGH and T2^LOW/T17^LOW.
• T2^HIGH was the least common endotype.
• Multiple pathways in T2^HIGH and T17^HIGH asthma may indicate new targets for treatment.

SAN DIEGO — Nasal sampling revealed three asthma endotypes among minoritized youth that could be potential targets for treatment, according to an abstract presented at the American Thoracic Society International Conference.

Prior studies have used bronchial epithelial gene expression to identify T2^HIGH, T17^HIGH and T2^LOW/T17^LOW endotypes, which are distinguished by different inflammatory mechanisms, among adults, Molin Yue, MS, PhD candidate, bioinformatics, University of Pittsburgh, said during his presentation.

“We aimed to replicate these findings in children using noninvasive nasal samples to differentiate endotypes based on gene expression, aiming to enhance the understanding and management of childhood asthma,” Yue said.

Molin Yue

Yue and his colleagues began with the 6-week Stress and Treatment Response in Puerto Rican and African American Children with Asthma (STAR) study of violence-related stress and response to inhaled corticosteroids in youth aged 8 to 20 years with asthma (n = 156) as their discovery cohort.

The replication cohorts included the Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) case-control study of asthma among youth aged 9 to 20 years (n = 237) and the Vitamin D Kids Asthma (VDKA) randomized clinical trial of vitamin D supplementation for asthma exacerbation prevention in children aged 6 to 16 years (n = 48).

“In all studies, participants could not have received systematic steroids for 4 weeks prior to nasal sample collection,” Yue said.

The researchers used eight gene markers to differentiate endotypes, including POSTN, CLCA1 and SERPINB2 for T2 and CXCL1, CXCL2, CXCL3, CSF3 and IL8 for T17.

“By K-means cluster analysis, using the eight marker genes, we were able to identify three clusters, labeled as T2^HIGH, T17^HIGH and T2^LOW/T17^LOW,” Yue said. “To make our results more robust, we also validated the cluster by other clustering methods.”

The researchers then compared demographic and clinical characteristics as well as biomarkers and lung function measures across these three clusters in each study. Also, they conducted a meta-analysis of differentially expressed genes (DEGs) via a whole genome transcriptomic profile with enriched canonical pathways.

Patients with T2^HIGH profiles accounted for approximately 23% to 29% of the population across the three studies, T17^HIGH profiles accounted for about 35% to 47%, and the T2^LOW/T17^LOW were about 30% to 38%.

“For the validation analysis, over 80% of the participants in all studies were assigned to the same endotype group in all high clustering analyses,” Yue said.

In STAR, median ages included 14.2 years for the T2^HIGH group (n = 40), 13.2 years for the T17^HIGH group (n = 57) and 15.1 years for the T2^LOW/T17^LOW group (n = 59).

Also, 57.5% (n = 23) of the T2^HIGH group, 21.1% (n = 12) of the T17^HIGH group and 15.3% (n = 9) of the T2^LOW/T17^LOW group in STAR were Puerto Rican (P < .05).

Percentages of Black patients in STAR included 42.5% (n = 17) of the T2^HIGH group, 78.9% (n = 45) of the T17^HIGH group and 84.7% (n = 50) of the T2^LOW/T17^LOW group (P < .05).

Percentages of patients with annual household incomes of $15,000 and higher included 62.9% (n = 22) of the T2^HIGH group, 31.9% (n = 15) of the T17^HIGH group and 43.5% (n = 20) of the T2^LOW/T17^LOW group (P < .05).

Physician-diagnosed allergic rhinitis was present in 42.1% (n = 16) of the T2^HIGH group, 12% (n = 6) of the T17^HIGH group and 31.5% (n = 17) of the T2^LOW/T17^LOW group (P < .05).

Additionally, percentages of patients with one or more asthma-related visit to the ED or urgent care in the previous year included 66.7% (n = 26) of the T2^HIGH group, 46.9% (n = 23) of the T17^HIGH group and 29.6% (n = 16) of the T2^LOW/T17^LOW group (P < .05).

Across all three studies, the T2^HIGH groups had higher total IgE and eosinophil counts than the T17^HIGH and T2^LOW/T17^LOW groups, with significant differences in STAR and in EVA-PR.

For example, serum total IgE in EVA-PR included 584 IU/mL in the T2^HIGH group, 216 IU/mL in the T17^HIGH group and 176 IU/mL in the T2^LOW/T17^LOW group (P < .05).

EVA-PR also reported blood eosinophil counts of 343 cells/ml for the T2^HIGH group, 187 cells/ml for the T17^HIGH group and 182 cells/ml for the T2^LOW/T17^LOW group (P < .05).

STAR was the only study that reported FeNO results, which included 59 ppb for the T2^HIGH group and 19 ppb for both the T17^HIGH group and the T2^LOW/T17^LOW groups (P < .05). There were no other significant differences in lung function between the three profiles across the three studies.

The DEG analysis revealed approximately 3,500 genes with false discovery rate (FDR) P values of less than .05 in a comparison of the T2^HIGH group with the T2^LOW group, including CDH26, CISH, ALOX15, CST1, CST2 and ITLN1.

In a comparison of patients with T17^HIGH and those with T17^LOW, there were about 2,500 genes with FDR P values of less than .05, including CXCL2, CXCL3 and CSF3.

“So based on these differentiated genes, we performed a canonical pathway enrichment analysis on upregulated genes and identified enriched asthma at FDP P values less than .05,” Yue said.

The top 10 overrepresented pathways of the T2^HIGH and T17^HIGH profiles were related to cellular signaling, neutrophils and T17 signaling, Yue continued.

Overall, Yue said, these findings indicate three asthma endotypes in predominantly minoritized youth that were consistently observed across multiple studies, with T2^HIGH asthma the least common of the three.

“Finally, we identified multiple differentially expressed genes and pathways for T2^HIGH and T17^HIGH asthma, potentially offering new targets for endotype-specific treatment,” Yue said.