Gene coexpression networks reveal novel molecular endotypes in alpha-1 antitrypsin deficiency

Jen Hwa Chu, Wenlan Zang, Milica Vukmirovic, Xiting Yan, Taylor Adams, Giuseppe Deiuliis, Buqu Hu, Antun Mihaljinec, Jonas C. Schupp, Michael J. Becich, Harry Hochheiser, Kevin F. Gibson, Edward S. Chen, Alison Morris, Joseph K. Leader, Stephen R. Wisniewski, Yingze Zhang, Frank C. Sciurba, Ronald G. Collman, Robert SandhausErica L. Herzog, Karen C. Patterson, Maor Sauler, Charlie Strange, Naftali Kaminski

Research output: Contribution to journalArticlepeer-review


Background Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals. Methods We performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects' clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay. Result We observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns. Conclusions We successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals' genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.

Original languageEnglish (US)
Pages (from-to)134-143
Number of pages10
Issue number2
StatePublished - Feb 1 2021


  • COPD mechanisms
  • alpha1 antitrypsin deficiency

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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