title: Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction.
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: FEV(1)% predicted, FEV(1)/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 FEV(1)% predicted (n=169) and FEV(1)/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.
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lamontagne
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada Department of Molecular Medicine, Laval University, Québec, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.affiliation: Division of Computational Biomedicine, Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Steiling
authors.affiliation: Division of Computational Biomedicine, Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Campbell
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
authors.forename: Massimo
authors.initials: M
authors.lastname: Conti
authors.affiliation: University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Sherwood
authors.affiliation: University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: Department of Pulmonology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sandford
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.affiliation: Division of Computational Biomedicine, Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.affiliation: Division of Computational Biomedicine, Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.affiliation: University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: Merck & Co Inc, Rahway, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Nickle
authors.affiliation: University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: Department of Pulmonology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
mesh_terms: D055316:Cystatin C / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics*; D015203:Reproducibility of Results; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C497867:CD22 protein, human; C525030:CST3 protein, human; D055316:Cystatin C; D012333:RNA, Messenger; D051918:Sialic Acid Binding Ig-like Lectin 2
keywords: COPD Pathology; Emphysema