Description
Rationale:Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that predisposes to early onset pulmonary emphysema and airways obstruction. The exact mechanism through which AATD leads to lung disease is incompletely understood.
Objectives: To investigate the effect of AAT genotype and augmentation therapy on bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMC) transcriptome, while examining the link between gene expression profiles, and clinical features of AATD.
Methods: We performed RNA-Seq on RNA extracted from BAL and PBMC on samples obtained from 89 AATD patients enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to identify genes and gene networks associated with AATD phenotypes. WGCNA gene modules were used in clustering analysis to examine novel clusters of AATD patients.
Measurements and Main Results:Differentially expressed genes were found in BAL and PBMC samples when testing the effect of genotype and augmentation therapy. Applying WGCNA on BAL samples, we identified a module which was correlated with multiple clinical variables and functionally enriched with numerous immune system pathways. We also identified three clusters of patients with distinct clinical features within the AATD phenotype based on expression profiles of this module. Severalgene markers of COPD exacerbation were differentially expressed across these clusters in PBMC samples.
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Gene Co-expression Networks Analysis Reveal Novel Molecular Endotypes in Alpha-1 Antitrypsin Deficiency
Rationale:Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that predisposes to early onset pulmonary emphysema and airways obstruction. The exact mechanism through which AATD leads to lung disease is incompletely understood.
Objectives: To investigate the effect of AAT genotype and augmentation therapy on bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMC) transcriptome, while examining the link between gene expression profiles, and clinical features of AATD.
Methods: We performed RNA-Seq on RNA extracted from BAL and PBMC on samples obtained from 89 AATD patients enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to identify genes and gene networks associated with AATD phenotypes. WGCNA gene modules were used in clustering analysis to examine novel clusters of AATD patients.
Measurements and Main Results:Differentially expressed genes were found in BAL and PBMC samples when testing the effect of genotype and augmentation therapy. Applying WGCNA on BAL samples, we identified a module which was correlated with multiple clinical variables and functionally enriched with numerous immune system pathways. We also identified three clusters of patients with distinct clinical features within the AATD phenotype based on expression profiles of this module. Severalgene markers of COPD exacerbation were differentially expressed across these clusters in PBMC samples.