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Original article
Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction
  1. Maxime Lamontagne1,
  2. Wim Timens2,
  3. Ke Hao3,
  4. Yohan Bossé1,4,
  5. Michel Laviolette1,
  6. Katrina Steiling5,
  7. Joshua D Campbell5,
  8. Christian Couture1,
  9. Massimo Conti1,
  10. Karen Sherwood6,
  11. James C Hogg6,7,
  12. Corry-Anke Brandsma2,
  13. Maarten van den Berge8,
  14. Andrew Sandford6,9,
  15. Stephen Lam10,
  16. Marc E Lenburg5,
  17. Avrum Spira5,
  18. Peter D Paré6,9,
  19. David Nickle11,
  20. Don D Sin6,9,
  21. Dirkje S Postma8
  1. 1Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada
  2. 2Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands
  3. 3Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, New York, USA
  4. 4Department of Molecular Medicine, Laval University, Québec, Canada
  5. 5Division of Computational Biomedicine, Bioinformatics Program, Boston University, Boston, Massachusetts, USA
  6. 6University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada
  7. 7Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  8. 8Department of Pulmonology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands
  9. 9Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  10. 10British Columbia Cancer Agency, Vancouver, British Columbia, Canada
  11. 11Merck & Co Inc, Rahway, New Jersey, USA
  1. Correspondence to Professor Dirkje S Postma, University of Groningen, University Medical Center Groningen, Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, AA11, Hanzeplein, PO Box 30001, Groningen 9700 RB, The Netherlands; d.s.postma{at}umcg.nl

Abstract

Background COPD is a complex chronic disease with poorly understood pathogenesis. Integrative genomic approaches have the potential to elucidate the biological networks underlying COPD and lung function. We recently combined genome-wide genotyping and gene expression in 1111 human lung specimens to map expression quantitative trait loci (eQTL).

Objective To determine causal associations between COPD and lung function-associated single nucleotide polymorphisms (SNPs) and lung tissue gene expression changes in our lung eQTL dataset.

Methods We evaluated causality between SNPs and gene expression for three COPD phenotypes: FEV1% predicted, FEV1/FVC and COPD as a categorical variable. Different models were assessed in the three cohorts independently and in a meta-analysis. SNPs associated with a COPD phenotype and gene expression were subjected to causal pathway modelling and manual curation. In silico analyses evaluated functional enrichment of biological pathways among newly identified causal genes. Biologically relevant causal genes were validated in two separate gene expression datasets of lung tissues and bronchial airway brushings.

Results High reliability causal relations were found in SNP–mRNA–phenotype triplets for FEV1% predicted (n=169) and FEV1/FVC (n=80). Several genes of potential biological relevance for COPD were revealed. eQTL-SNPs upregulating cystatin C (CST3) and CD22 were associated with worse lung function. Signalling pathways enriched with causal genes included xenobiotic metabolism, apoptosis, protease–antiprotease and oxidant–antioxidant balance.

Conclusions By using integrative genomics and analysing the relationships of COPD phenotypes with SNPs and gene expression in lung tissue, we identified CST3 and CD22 as potential causal genes for airflow obstruction. This study also augmented the understanding of previously described COPD pathways.

  • COPD Pathology
  • Emphysema

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