Transcriptome-wide association study of sex effects identifies sex-specific nasal epithelial gene expression profiles for total IgE.

Abstract

Asthma is the most common chronic respiratory disease in children, with known sex differences in prevalence and severity that shift after puberty. Total IgE, a marker of type 2-high asthma, also differs by sex and age and may contribute to these disparities. We tested whether nasal epithelial gene expression differs by sex and interacts with total IgE in ways that may inform asthma pathogenesis in a transcriptome-wide association study in nasal epithelial samples from participants in two cohorts: EVA-PR (including 398 Puerto Rican youths aged 12-20 years) and PIAMA (including 303 Dutch adolescents aged 16 years). Differential expression analysis by sex identified 406 genes at a false discovery rate-adjusted P value of <.05, with 225 upregulated and 181 downregulated in female compared to male subjects. Top differentially expressed genes included hormone- and immune-related genes such as THRB, IL17REL, and CD207. Among these, 6 genes (MNDA, IFIT1, IFIT2, SLC22A17, JAG2, and MT3) showed significant sex-by-total IgE interaction effects on expression. Pathway enrichment analyses revealed that female subjects had activation of eukaryotic translation pathways (eg, EIF2 signaling), while male subjects showed activation of immune-related pathways (eg, interferon signaling). Additionally, 19 pathways were enriched in the sex-by-IgE interaction model, including TREM1 and cytokine storm signaling. Our findings provide new insights into sex-specific regulation of gene expression in airway epithelium and its interaction with total IgE, helping to explain observed sex differences in asthma. This underscores the need to consider sex as a biological variable in asthma research and points to potential targets for precision medicine approaches.