Sex-biased Gene Expression Underlies Immune Dysfunction in Asthma

Asthma prevalence and severity differs between male and female individuals across the lifespan. Prepubescent boys are more likely to experience asthma, but girls are disproportionately affected after puberty, with greater symptom burden and decreased type 2 inflammation. However, because the human male and female genomes are almost identical, it is especially difficult to identify differentially expressed genes by sex to account for differences in disease susceptibility and manifestations without large sample sizes. Although several genes and genetic polymorphisms lead to sex-specific effects in asthma risk, the effects of sex-biased gene expression on clinical features within patients with asthma remain understudied. In this study, we characterized gene expression differences between female and male individuals through meta-analysis of transcriptomes of blood samples from adult patients with and without asthma in a large gene expression database (n = 3,639; 56% female). A separate, local validation cohort (n = 132; 78% female) identified clinical correlations with expression levels of sex-biased expressed genes. We identified 61 genes differentially expressed by sex in circulating immune cells that are unique to adult subjects with asthma and correlate with important clinical features of asthma. These genes are implicated in lymphocyte proliferation and differentiation as well as innate and adaptive immune allergic responses in the lung. In addition, similar transcriptional meta-analyses of pediatric asthma demonstrated age-specific gene expression effects. In summary, our findings support a sex-specific inflammatory architecture in asthma that is associated with differential gene expression in the blood and is age-specific.