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Am J Respir Cell Mol Biol. 2017 Oct;57(4):411-418. doi: 10.1165/rcmb.2016-0284OC.

Integrative Genomics of Emphysema-Associated Genes Reveals Potential Disease Biomarkers.

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1 The University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
2 Department of Molecular Medicine.
3 Institut Universitaire de Cardiologie et de Pneumologie de Québec, and.
4 Department of Molecular Biology, Medical Biochemistry, and Pathology, Laval University, Québec, Quebec, Canada.
5 Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts.
6 Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
7 Department of Pulmonology, and.
8 Department of Pathology and Medical Biology, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
9 Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.
10 GlaxoSmithKline, King of Prussia, Pennsylvania.
11 Division of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
12 Clinical Discovery Unit, Early Clinical Development, AstraZeneca, Cambridge, United Kingdom.
13 Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
14 Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
15 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
16 Fundacio Clinic per a la Recerca Biomedica, Barcelona, Spain.
17 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and.
18 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.


Chronic obstructive pulmonary disease is the third leading cause of death worldwide. Gene expression profiling across multiple regions of the same lung identified genes significantly related to emphysema. We sought to determine whether the lung and epithelial expression of 127 emphysema-related genes was also related to lung function in independent cohorts, and whether any of these genes could be used as biomarkers in the peripheral blood of patients with chronic obstructive pulmonary disease. To that end, we examined whether the expression levels of these genes were under genetic control in lung tissue (n = 1,111). We then determined whether the mRNA levels of these genes in lung tissue (n = 727), small airway epithelial cells (n = 238), and peripheral blood (n = 620) were significantly related to lung function measurements. The expression of 63 of the 127 genes (50%) was under genetic control in lung tissue. The lung and epithelial mRNA expression of a subset of the emphysema-associated genes, including ASRGL1, LPHN2, and EDNRB, was strongly associated with lung function. In peripheral blood, the expression of 40 genes was significantly associated with lung function. Twenty-nine of these genes (73%) were also associated with lung function in lung tissue, but with the opposite direction of effect for 24 of the 29 genes, including those involved in hypoxia and B cell-related responses. The integrative genomics approach uncovered a significant overlap of emphysema genes associations with lung function between lung and blood with opposite directions between the two. These results support the use of peripheral blood to detect disease biomarkers.


FEV1; biomarker; blood; lung; mRNA

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