. 2014 Oct;44(4):860-72.

doi: 10.1183/09031936.00001914. Epub 2014 Jul 3.

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

Joanna Smolonska¹, Gerard H Koppelman², Cisca Wijmenga³, Judith M Vonk⁴, Pieter Zanen⁵, Marcel Bruinenberg³, Ivan Curjuric⁶, Medea Imboden⁶, Gian-Andri Thun⁶, Lude Franke³, Nicole M Probst-Hensch⁶, Peter Nürnberg⁷, Roland A Riemersma⁸, Constant P van Schayck⁹, Daan W Loth¹⁰, Guy G Brusselle¹¹, Bruno H Stricker¹², Albert Hofman¹³, André G Uitterlinden¹⁴, Lies Lahousse¹⁵, Stephanie J London¹⁶, Laura R Loehr¹⁷, Ani Manichaikul¹⁸, R Graham Barr¹⁹, Kathleen M Donohue¹⁹, Stephen S Rich²⁰, Peter Pare²¹, Yohan Bossé²², Ke Hao²³, Maarten van den Berge⁸, Harry J M Groen²⁴, Jan-Willem J Lammers⁵, Willem Mali²⁵, H Marike Boezen⁴, Dirkje S Postma²⁶

Affiliations

¹ Dept of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Dept of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands.
² GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands Dept of Paediatric Pulmonology and Paediatric Allergology, Beatrix Children's Hospital, University Medical Center, University of Groningen, Groningen, The Netherlands.
³ Dept of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴ Dept of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands.
⁵ Dept of Pulmonology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁶ Dept of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
⁷ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁸ GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹ Dept of General Practice, University of Maastricht, Maastricht, The Netherlands.
¹⁰ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Netherlands Healthcare Inspectorate, The Hague, The Netherlands.
¹¹ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium Dept of Respiratory Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹² Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Netherlands Healthcare Inspectorate, The Hague, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
¹³ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
¹⁴ Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands Dept of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹⁵ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁶ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA.
¹⁷ University of North Carolina, Chapel Hill, NC, USA.
¹⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Dept of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA.
¹⁹ Dept of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
²⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²¹ Respiratory Division, Dept of Medicine, University of British Columbia James Hogg Research Centre, St Paul's Hospital, Vancouver, BC, Canada.
²² Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Dept of Molecular Medicine, Laval University, Québec, QC, Canada.
²³ Dept of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, NY, USA.
²⁴ Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁵ Dept of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.
²⁶ GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands d.s.postma@umcg.nl.

PMID: 24993907
PMCID: PMC4217133
DOI: 10.1183/09031936.00001914

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

Joanna Smolonska et al. Eur Respir J. 2014 Oct.

. 2014 Oct;44(4):860-72.

doi: 10.1183/09031936.00001914. Epub 2014 Jul 3.

Authors

Affiliations

¹ Dept of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Dept of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands.
² GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands Dept of Paediatric Pulmonology and Paediatric Allergology, Beatrix Children's Hospital, University Medical Center, University of Groningen, Groningen, The Netherlands.
³ Dept of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴ Dept of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands.
⁵ Dept of Pulmonology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁶ Dept of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
⁷ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁸ GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹ Dept of General Practice, University of Maastricht, Maastricht, The Netherlands.
¹⁰ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Netherlands Healthcare Inspectorate, The Hague, The Netherlands.
¹¹ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium Dept of Respiratory Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹² Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Netherlands Healthcare Inspectorate, The Hague, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
¹³ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
¹⁴ Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands Dept of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹⁵ Dept of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁶ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA.
¹⁷ University of North Carolina, Chapel Hill, NC, USA.
¹⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA Dept of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA.
¹⁹ Dept of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
²⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²¹ Respiratory Division, Dept of Medicine, University of British Columbia James Hogg Research Centre, St Paul's Hospital, Vancouver, BC, Canada.
²² Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Dept of Molecular Medicine, Laval University, Québec, QC, Canada.
²³ Dept of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, NY, USA.
²⁴ Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁵ Dept of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.
²⁶ GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands d.s.postma@umcg.nl.

PMID: 24993907
PMCID: PMC4217133
DOI: 10.1183/09031936.00001914

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background ("Dutch hypothesis"). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κβ pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10(-9)). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-κβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.

The content of this work is not subject to copyright. Designand branding are ©ERS 2014.

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Figures

**Figure 2**
Regional association plots for *DDX1*, *COMMD10* and *GNG5P5* loci. The plots were generated using R and regional association plot script from BROAD institute

**Figure 3**
Forest plots of the three top SNPs in the meta-analysis of the asthma and COPD cohorts.

**Figure 4**
eQTLs identified for *COMMD10* SNPs. Left panel: blood eQTLs, right panel: lung eQTLs. Order on x-axis is from non-risk homozygote, heterozygote and risk homozygote for all three eQTLs. Note: in lung tissue dataset, the risk homozygotes were not present.

**Figure 5**
Gene enrichment plot using *DDX1* and *COMMD10* genes as a query

See this image and copyright information in PMC

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Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

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Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

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