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Transcriptome-wide association study of sex effects identifies sex-specific nasal epithelial gene expression profiles
Molin Yue1, Yidan Sun2, Yueh Ying Han3
1Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa; Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, Pa.
Background:
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.
Methods:
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).
Results:
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.
Conclusions:
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.
