Format

Send to

Choose Destination
Lancet Respir Med. 2015 Oct;3(10):782-95. doi: 10.1016/S2213-2600(15)00380-X. Epub 2015 Sep 21.

Molecular mechanisms underlying variations in lung function: a systems genetics analysis.

Author information

1
University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
2
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Department of Molecular Medicine, Laval University, Québec, QC, Canada; Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, QC, Canada.
4
Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, MA, USA.
5
University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, Netherlands.
6
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, QC, Canada.
7
University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada; Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
8
University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
9
Department of Pathology and Medical Biology, GRIAC Research Institute, University of Groningen, Groningen, Netherlands.
10
Department of Twin Research and Genetic Epidemiology, King's College, London, UK.
11
Department of Public Health, and Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
12
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
13
Busselton Population Medical Research Institute, Busselton, WA, Australia; PathWest Laboratory Medicine of Western Australia, Nedlands, WA, Australia; School of Population Health and School of Pahology and Laboratory Medicine, University of Western Australia, Nedlands, WA, Australia.
14
Research Unit of Molecular Epidemiology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Genetic Epidemiology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
15
Institute of Epidemiology I, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany.
16
University Hospital, Department of Internal Medicine B, Greifswald, Germany.
17
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
18
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK; Faculty of Medicine, University of Split, Croatia.
19
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College, London, UK; Center for Life Course Epidemiology, Faculty of Medicine, Biocenter Oulu, and Unit of Primary Care, Oulu University Hospital, University of Oulu, Oulu, Finland.
20
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge UK.
21
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College, London, UK; Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College, London, UK.
22
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
23
Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
24
Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; University of North Carolina Center for Genome Sciences, Chapel Hill, NC, USA.
25
Departments of Epidemiology and Respiratory Medicine, Erasmus MC, Rotterdam, Netherlands.
26
Departments of Epidemiology and Respiratory Medicine, Erasmus MC, Rotterdam, Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
27
Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
28
Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
29
Human Genetics & Computational Biomedicine, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
30
Pulmonary Center, Boston University School of Medicine, Boston, MA, USA; NHLBI Framingham Heart Study, Framingham, MA, USA.
31
Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medical College, NY, USA.
32
Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
33
University of Leicester, Genetic Epidemiology Group, Department of Health Sciences, Leicester, UK; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
34
Computational Medicine Core, Center for Lung Biology, University of Washington, Seattle, WA, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
35
Population Health Research Institute, St George's, University of London, London, UK.
36
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
37
University of Nottingham Division of Respiratory Medicine, University Hospital of Nottingham, Nottingham, UK.
38
University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada; Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: peter.pare@hli.ubc.ca.

Erratum in

Abstract

BACKGROUND:

Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48,201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs.

METHODS:

The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature.

FINDINGS:

SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD.

INTERPRETATION:

The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico.

FUNDING:

The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.

Comment in

PMID:
26404118
PMCID:
PMC5021067
DOI:
10.1016/S2213-2600(15)00380-X
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Declaration of interests DCN is an employee of Merck and Co. DSP reports grants to the university and consultancy fees to the university from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, and TEVA outside of the submitted work. DDS reports personal fees from Amgen, grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, grants from Novartis, outside of the submitted work. DJ reports grants from the European Union. IPH reports grants from MRC during the conduct of the study. JK reports grants from the Academy of Finland and from the European Union during the conduct of the study, and personal fees from Pfizer, outside of the submitted work. JBW is an employee of Pfizer. PAC reports grants from National Institutes of Health during the conduct of the study. ML has received payments from Boston Scientific, AstraZeneca, and Merck for lectures and from GSK for a consultants’ meeting. WTi reports personal fees from Pfizer, GSK, Chiesi, and Roche Diagnostics/Ventana, and grants from Dutch Asthma Fund, outside of the submitted work. WTa reports personal fees from Boehringer Ingelheim Pharmaceuticals, outside of the submitted work. All other authors declare no competing interests.

Publication types, MeSH terms, Grant support

Publication types

MeSH terms

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center