Abstract
Epidemiological studies have shown that female smokers are at higher risk of chronic obstructive pulmonary disease (COPD). Female patients have worse symptoms and health status and increased risk of exacerbations. We determined the differences in the transcriptome of the airway epithelium between males and females, as well the sex-by-smoking interaction. We processed public gene expression data of human airway epithelium into a discovery cohort of 211 subjects (never smokers n = 68; current smokers n = 143) and two replication cohorts of 104 subjects (21 never, 52 current, and 31 former smokers) and 238 subjects (99 current and 139 former smokers. We analyzed gene differential expression with smoking status, sex, and smoking-by-sex interaction and used network approaches for modules’ level analyses. We identified and replicated two differentially expressed modules between the sexes in response to smoking with genes located throughout the autosomes and not restricted to sex chromosomes. The two modules were enriched in autophagy (up-regulated in female smokers) and response to virus and type 1 interferon signaling pathways which were down-regulated in female smokers compared to males. The results offer insights into the molecular mechanisms of the sexually dimorphic effect of smoking, potentially enabling a precision medicine approach to smoking related lung diseases.
Highlights
Chronic obstructive pulmonary disease (COPD) affects more than 300 million people and is the 3rd leading cause of death worldwide[1]
To further understand the mechanisms underlying the sexual dimorphism in the pathogenesis of smoking related lung diseases, we examined the effects of sex, and its interaction with cigarette smoking, on the transcriptome of human airway epithelial cells
We analyzed the differential transcriptomics of human airway epithelium associated with smoking as well as the transcriptomics of smoking differentially between males and females
Summary
Chronic obstructive pulmonary disease (COPD) affects more than 300 million people and is the 3rd leading cause of death worldwide[1]. Our group has reported previously that female smokers experience a heightened risk of COPD, following menopause[5]. These data have been validated in a study involving 149,075 women and 100,252 men in the UK Biobank[6]. There is a growing body of evidence from histological, imaging and animal models to support the notion that females have more airways disease and less emphysema compared to male COPD patients[8,9]. Since some metabolites of nicotine may be toxic, the sex-related differences in xenometabolism maybe an important driver of increased female susceptibility to COPD12,13. To further understand the mechanisms underlying the sexual dimorphism in the pathogenesis of smoking related lung diseases, we examined the effects of sex, and its interaction with cigarette smoking, on the transcriptome of human airway epithelial cells
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