Dataset Information

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking.

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.

SUBMITTER: Yang CX

PROVIDER: S-EPMC6879662 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking.

Yang Chen Xi CX Shi Henry H Ding Irving I Milne Stephen S Hernandez Cordero Ana I AI Yang Cheng Wei Tony CWT Kim Edward Kyoo-Hoon EK Hackett Tillie-Louise TL Leung Janice J Sin Don D DD Obeidat Ma'en M

Scientific reports 20191126 1

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 smok ...[more]

PMID: 31772224

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Project description:BackgroundThe production of gamma-amino butyric acid (GABA) is dependent on glutamate decarboxylases (GAD65 and GAD67), the enzymes that catalyze the decarboxylation of glutamate to GABA. Based on studies suggesting a role of the airway epithelial GABAergic system in asthma-related mucus overproduction, we hypothesized that cigarette smoking, another disorder associated with increased mucus production, may modulate GABAergic system-related gene expression levels in the airway epithelium.MethodsWe assessed expression of the GABAergic system in human airway epithelium obtained using bronchoscopy to sample the epithelium and microarrays to evaluate gene expression. RT-PCR was used to confirm gene expression of GABAergic system gene in large and small airway epithelium from heathy nonsmokers and healthy smokers. The differences in the GABAergic system gene was further confirmed by TaqMan, immunohistochemistry and Western analysis.ResultsThe data demonstrate there is a complete GABAergic system expressed in the large and small human airway epithelium, including glutamate decarboxylase, GABA receptors, transporters and catabolism enzymes. Interestingly, of the entire GABAergic system, smoking modified only the expression of GAD67, with marked up-regulation of GAD67 gene expression in both large (4.1-fold increase, p < 0.01) and small airway epithelium of healthy smokers (6.3-fold increase, p < 0.01). At the protein level, Western analysis confirmed the increased expression of GAD67 in airway epithelium of healthy smokers compared to healthy nonsmokers (p < 0.05). There was a significant positive correlation between GAD67 and MUC5AC gene expression in both large and small airway epithelium (p < 0.01), implying a link between GAD67 and mucin overproduction in association with smoking.ConclusionsIn the context that GAD67 is the rate limiting enzyme in GABA synthesis, the correlation of GAD67 gene expression with MUC5AC expressions suggests that the up-regulation of airway epithelium expression of GAD67 may contribute to the increase in mucus production observed in association with cigarette smoking.Trial registrationNCT00224198; NCT00224185.

Dataset Information

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking.

Publications

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking.

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