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Original research
Gene coexpression networks reveal novel molecular endotypes in alpha-1 antitrypsin deficiency
  1. Jen-hwa Chu1,2,
  2. Wenlan Zang2,
  3. Milica Vukmirovic1,3,
  4. Xiting Yan1,2,
  5. Taylor Adams1,
  6. Giuseppe DeIuliis1,
  7. Buqu Hu1,
  8. Antun Mihaljinec1,
  9. Jonas C Schupp1,
  10. Michael J Becich4,
  11. Harry Hochheiser4,
  12. Kevin F Gibson5,
  13. Edward S Chen6,
  14. Alison Morris5,
  15. Joseph K Leader7,
  16. Stephen R Wisniewski8,
  17. Yingze Zhang5,
  18. Frank C Sciurba5,
  19. Ronald G Collman9,10,
  20. Robert Sandhaus11,
  21. Erica L Herzog1,
  22. Karen C Patterson10,12,
  23. Maor Sauler1,
  24. Charlie Strange13,
  25. Naftali Kaminski1
  26. on behalf of the GRADS Investigators
  1. 1 Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
  2. 2 Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut, USA
  3. 3 Department of Medicine, Division of Respirology, McMaster University, Hamilton, Ontario, Canada
  4. 4 Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  5. 5 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  6. 6 Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  7. 7 Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  8. 8 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
  9. 9 Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  10. 10 Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  11. 11 Department of Medicine, National Jewish Health, Denver, Colorado, USA
  12. 12 Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brigton, UK
  13. 13 Medical University of South Carolina, Charleston, South Carolina, USA
  1. Correspondence to Dr Jen-hwa Chu, Yale University School of Medicine, New Haven, CT 06520-8057, USA; jen-hwa.chu{at}


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.

  • alpha1 antitrypsin deficiency
  • COPD mechanisms

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  • J-hC, WZ and MV contributed equally.

  • Presented at Parts of this work were presented as abstracts in American Thoracic Society International Conference in San Diego, California, May 2018.

  • Contributors NK, RS, FCS, SRW and CS conceived and designed the experiments. ESC, RGC, RS, CS, MJB, HH, KFG, ELH and JKL participated in subject phenotyping and classification. KCP, RGC, NK, RS, CS, EM, MB, HH, KFG, ELH, RS and SRW supervised sample and data collection, MV, TA, and GD performed the RNA sequencing experiments. JCS performed the single cell RNA sequencing experiments. JC, WZ, NK, MV, XY, BH, AM and MS analysed the data. NK, CS and FCS supervised the analytic plan. JC, WZ and MV wrote the manuscript with input from all other authors. All authors have read and approved the manuscript.

  • Funding This work is supported by NIH/NHLBI grant U01HL112707.

  • Patient consent for publication Not required.

  • Ethics approval The recruitment and consenting procedures were approved by the local Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. RNAseq data described in this paper has been deposited in the NCBI Gene Expression Omnibus (GEO) under accession code GSE109515.