Long-Term PM_2.5 Exposure and Upregulation of CLCA1 Expression in Nasal Epithelium from Youth with Asthma

Rationale: Little is known about long-term particulate matter 92.5 μm in aerodynamic diameter (PM_2.5) exposure and airway epithelial gene expression. Objectives: To test for association between long-term PM_2.5 exposure and nasal epithelial gene expression in youth with asthma. Methods: Transcriptome-wide association study (TWAS) of long-term PM_2.5 in nasal epithelium from youth aged 6-20 years in the 1) Epigenetic Variation and Childhood Asthma in Puerto Ricans study (n = 182), 2) Vitamin D Kids Asthma Study (n = 58), and 3) Stress and Treatment Response in Puerto Rican and African American Children with Asthma study (n = 81). Satellite hybrid models were used to estimate PM_2.5 exposure in the prior year at each participant's residence. Multivariable negative binomial regression was used for each TWAS, adjusting for age, sex, and other covariates. A meta-analysis of all TWAS results was then conducted using an inverse variance-weighted average approach. Results: Most participants (∼95%) in the meta-analysis of TWAS for PM_2.5 exposure identified as Puerto Rican or Black. Long-term PM_2.5 was associated with 1) upregulated expression of CLCA1 (calcium-activated chloride channel regulator 1; false discovery rate-adjusted P [FDR-P] = 0.008), SYCP2 (synaptonemal complex protein 2; FDR-P = 0.01), and CYP2A6 (cytochrome p450 family 2 subfamily A member 6; FDR-P = 0.02); and 2) downregulated expression of EDAR (ectodysplasin A receptor; FDR-P = 0.01). In a meta-analysis, CLCA1 upregulation was associated with one or more positive allergen-specific IgE (FDR-P < 0.001) and increased blood eosinophils (FDR-P < 0.001) and total IgE (FDR-P < 0.001). Conclusions: In a meta-analysis of TWASs in predominantly Puerto Rican and Black youth with asthma, long-term PM_2.5 exposure was associated with upregulated airway epithelial CLCA1 expression, in turn linked to biomarkers of T2-high immunity.