Multi‐omic integration reveals alterations in nasal mucosal biology that mediate air pollutant effects on allergic rhinitis

• Published in: Allergy (Copenhagen) 2024-11, Vol.79 (11), p.3047-3061
• Main Authors: Irizar, Haritz, Chun, Yoojin, Hsu, Hsiao‐Hsien Leon, Li, Yan‐Chak, Zhang, Lingdi, Arditi, Zoe, Grishina, Galina, Grishin, Alexander, Vicencio, Alfin, Pandey, Gaurav, Bunyavanich, Supinda
• Format: Article
• Language: English
• Subjects: Acrylic acid; Adolescent; Adult; Air Pollutants - adverse effects; Air pollution; Allergic rhinitis; allergy; Antimony; Case-Control Studies; causal mediation; Cell activation; Child; DNA fingerprinting; DNA Methylation; Environmental Exposure - adverse effects; epigenome; Female; Gene expression; Gene Expression Profiling; Genomics - methods; Hay fever; Humans; Inflammation; Male; Mucosa; Multiomics; multi‐omic; nasal; Nasal Mucosa - immunology; Nasal Mucosa - metabolism; Phosphine; Pollutants; Rhinitis; Rhinitis, Allergic - etiology; Rhinitis, Allergic - immunology; systems biology; Transcription activation; Transcriptome; Transcriptomes; Young Adult
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.16174

Background Allergic rhinitis is a common inflammatory condition of the nasal mucosa that imposes a considerable health burden. Air pollution has been observed to increase the risk of developing allergic rhinitis. We addressed the hypotheses that early life exposure to air toxics is associated with developing allergic rhinitis, and that these effects are mediated by DNA methylation and gene expression in the nasal mucosa. Methods In a case–control cohort of 505 participants, we geocoded participants' early life exposure to air toxics using data from the US Environmental Protection Agency, assessed physician diagnosis of allergic rhinitis by questionnaire, and collected nasal brushings for whole‐genome DNA methylation and transcriptome profiling. We then performed a series of analyses including differential expression, Mendelian randomization, and causal mediation analyses to characterize relationships between early life air toxics, nasal DNA methylation, nasal gene expression, and allergic rhinitis. Results Among the 505 participants, 275 had allergic rhinitis. The mean age of the participants was 16.4 years (standard deviation = 9.5 years). Early life exposure to air toxics such as acrylic acid, phosphine, antimony compounds, and benzyl chloride was associated with developing allergic rhinitis. These air toxics exerted their effects by altering the nasal DNA methylation and nasal gene expression levels of genes involved in respiratory ciliary function, mast cell activation, pro‐inflammatory TGF‐β1 signaling, and the regulation of myeloid immune cell function. Conclusions Our results expand the range of air pollutants implicated in allergic rhinitis and shed light on their underlying biological mechanisms in nasal mucosa. In a cohort of 505 participants, we examined the effects of air toxics on allergic rhinitis development and their mediation by nasal DNA methylation and nasal gene expression. Multi‐omic integration revealed methylation and gene expression paths involving THBS1 and RHOH mediating the effects of acrylic acid and phosphine on AR development. Increased mast cell degranulation and TGF‐β1 activation are potential mechanisms of air toxic effects on AR development.Abbreviations: FcεRI, Fc epsilon RI; IgE, immunoglobulin E; IL‐33, interleukin 33; RHOH, ras homolog family member H; ST2, suppression of tumorigenicity 2; TGF‐β1, transforming growth factor beta 1; THBS1, thrombospondin 1.