Meta-Analysis

. 2014 Apr 8;9(4):e91621.

doi: 10.1371/journal.pone.0091621. eCollection 2014.

Susceptibility to chronic mucus hypersecretion, a genome wide association study

Akkelies E Dijkstra¹, Joanna Smolonska², Maarten van den Berge¹, Ciska Wijmenga³, Pieter Zanen⁴, Marjan A Luinge⁵, Mathieu Platteel³, Jan-Willem Lammers⁴, Magnus Dahlback⁶, Kerrie Tosh⁷, Pieter S Hiemstra⁸, Peter J Sterk⁹, Avi Spira¹⁰, Jorgen Vestbo¹¹, Borge G Nordestgaard¹², Marianne Benn¹³, Sune F Nielsen¹⁴, Morten Dahl¹⁵, W Monique Verschuren¹⁶, H Susan J Picavet¹⁶, Henriette A Smit¹⁷, Michael Owsijewitsch¹⁸, Hans U Kauczor¹⁸, Harry J de Koning¹⁹, Eva Nizankowska-Mogilnicka²⁰, Filip Mejza²⁰, Pawel Nastalek²⁰, Cleo C van Diemen³, Michael H Cho²¹, Edwin K Silverman²¹, James D Crapo²², Terri H Beaty²³, David A Lomas²⁴, Per Bakke²⁵, Amund Gulsvik²⁵, Yohan Bossé²⁶, Ma'en Obeidat, Daan W Loth²⁷, Lies Lahousse²⁸, Fernando Rivadeneira²⁹, Andre G Uitterlinden²⁹, Andre Hofman³⁰, Bruno H Stricker²⁷, Guy G Brusselle²⁸, Cornelia M van Duijn³¹, Uilke Brouwer³², Gerard H Koppelman³³, Judith M Vonk³⁴, Martijn C Nawijn³², Harry J M Groen³⁵, Wim Timens⁵, H Marike Boezen³⁴, Dirkje S Postma¹; LifeLines Cohort study

Collaborators, Affiliations

Collaborators

LifeLines Cohort study:
B Z Alizadeh, R A de Boer, H M Boezen, M Bruinenberg, L Franke, P van der Harst, H L Hillege, M M van der Klauw, G Navis, J Ormel, D S Postma, J G M Rosmalen, J P Slaets, H Snieder, R P Stolk, B H R Wolffenbuttel, C Wijmenga

Affiliations

¹ University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands.
² University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
³ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
⁴ University of Utrecht, University Medical Center Utrecht, Department of Pulmonology, Utrecht, the Netherlands.
⁵ University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
⁶ AstraZeneca, R&D Mölndal, Mölndal, Sweden.
⁷ AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
⁸ Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands.
⁹ Department of Respiratory Medicine, University of Amsterdam, Amsterdam, the Netherlands.
¹⁰ Department of Medicine, Section of Computational Biomedicine, Boston University Medical Center, Boston, Massachusetts, United States of America.
¹¹ Odense University Hospital, Department of Respiratory Medicine J, and University of Southern Denmark, Clinical Institute, Odense, Denmark; Respiratory and Allergy Research Group, Manchester Academic Health Sciences Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, United Kingdom.
¹² The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁴ The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Center for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
¹⁷ Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, the Netherlands.
¹⁸ Department of Diagnostic and Interventional Radiology, University Hospital of Heidelberg, Heidelberg, Germany; Translational Lung Research Center (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
¹⁹ Department of Public Health, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
²⁰ Department of Respiratory Diseases, Jagiellonian University Medical College, Krakow, Poland.
²¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
²² Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado, United States of America.
²³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
²⁴ Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
²⁵ Department of Thoracic Medicine, Haukeland University, Hospital and Institute of Medicine, University of Bergen, Bergen, Norway.
²⁶ Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec City, Canada.
²⁷ Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; The Netherlands Healthcare Inspectorate, The Hague, the Netherlands.
²⁸ Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of respiratory medicine, University Hospital Ghent, Ghent, Belgium.
²⁹ Department of Internal medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
³⁰ Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
³¹ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.
³² University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
³³ University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Beatrix Childrens' Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, the Netherlands.
³⁴ University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.
³⁵ University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, the Netherlands.

PMID: 24714607
PMCID: PMC3979657
DOI: 10.1371/journal.pone.0091621

Meta-Analysis

Susceptibility to chronic mucus hypersecretion, a genome wide association study

Akkelies E Dijkstra et al. PLoS One. 2014.

. 2014 Apr 8;9(4):e91621.

doi: 10.1371/journal.pone.0091621. eCollection 2014.

Authors

Collaborators

LifeLines Cohort study:
B Z Alizadeh, R A de Boer, H M Boezen, M Bruinenberg, L Franke, P van der Harst, H L Hillege, M M van der Klauw, G Navis, J Ormel, D S Postma, J G M Rosmalen, J P Slaets, H Snieder, R P Stolk, B H R Wolffenbuttel, C Wijmenga

Affiliations

¹ University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands.
² University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
³ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
⁴ University of Utrecht, University Medical Center Utrecht, Department of Pulmonology, Utrecht, the Netherlands.
⁵ University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
⁶ AstraZeneca, R&D Mölndal, Mölndal, Sweden.
⁷ AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
⁸ Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands.
⁹ Department of Respiratory Medicine, University of Amsterdam, Amsterdam, the Netherlands.
¹⁰ Department of Medicine, Section of Computational Biomedicine, Boston University Medical Center, Boston, Massachusetts, United States of America.
¹¹ Odense University Hospital, Department of Respiratory Medicine J, and University of Southern Denmark, Clinical Institute, Odense, Denmark; Respiratory and Allergy Research Group, Manchester Academic Health Sciences Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, United Kingdom.
¹² The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁴ The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Center for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
¹⁷ Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, the Netherlands.
¹⁸ Department of Diagnostic and Interventional Radiology, University Hospital of Heidelberg, Heidelberg, Germany; Translational Lung Research Center (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
¹⁹ Department of Public Health, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
²⁰ Department of Respiratory Diseases, Jagiellonian University Medical College, Krakow, Poland.
²¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
²² Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado, United States of America.
²³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
²⁴ Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
²⁵ Department of Thoracic Medicine, Haukeland University, Hospital and Institute of Medicine, University of Bergen, Bergen, Norway.
²⁶ Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec City, Canada.
²⁷ Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; The Netherlands Healthcare Inspectorate, The Hague, the Netherlands.
²⁸ Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of respiratory medicine, University Hospital Ghent, Ghent, Belgium.
²⁹ Department of Internal medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
³⁰ Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
³¹ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.
³² University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
³³ University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Beatrix Childrens' Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, the Netherlands.
³⁴ University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.
³⁵ University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, the Netherlands.

PMID: 24714607
PMCID: PMC3979657
DOI: 10.1371/journal.pone.0091621

Erratum in

Correction: Susceptibility to chronic mucus hypersecretion, a genome wide association study.
Dijkstra AE, Smolonska J, van den Berge M, Wijmenga C, Zanen P, Luinge MA, Platteel M, Lammers JW, Dahlback M, Tosh K, Hiemstra PS, Sterk PJ, Spira A, Vestbo J, Nordestgaard BG, Benn M, Nielsen SF, Dahl M, Verschuren WM, Picavet HS, Smit HA, Owsijewitsch M, Kauczor HU, de Koning HJ, Nizankowska-Mogilnicka E, Mejza F, Nastalek P, van Diemen CC, Cho MH, Silverman EK, Crapo JD, Beaty TH, Lomas DA, Bakke P, Gulsvik A, Bossé Y, Obeidat M, Loth DW, Lahousse L, Rivadeneira F, Uitterlinden AG, Hofman A, Stricker BH, Brusselle GG, van Duijn CM, Brouwer U, Koppelman GH, Vonk JM, Nawijn MC, Groen HJ, Timens W, Boezen HM, Postma DS; LifeLines Cohort Study. Dijkstra AE, et al. PLoS One. 2015 May 29;10(5):e0129524. doi: 10.1371/journal.pone.0129524. eCollection 2015. PLoS One. 2015. PMID: 26024482 Free PMC article. No abstract available.

Abstract

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations.

Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP).

Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10(-9)) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture.

Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

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Conflict of interest statement

Competing Interests: Firms occurring more frequently are coded as follows: A = AstraZeneca; B = Chiesi; C = Merck; D = Boehringer Ingelheim; E = GlaxoSmithKline; F = Nycomed; G = TEVA Pharma; H = Roche; I = Siemens; J = Pfizer. M. Dahlback and K. Tosh are employees of A. The University of Groningen: money for D. S. Postma regarding an unrestricted educational grant for research from A and B, an unrestricted grant for W. Timens from C, a grant from the Dutch Asthma Foundation for W. Timens, and grants for G. H. Koppelman and D. S. Postma from the BBMRI-NL, The Dutch Asthma Foundation and the Stichting Astma Bestrijding, and fees for consultancies of D. S. Postma by A, D, B, E, F, and G, and payment for lectures from A, B, and G and for consultancies of H. J. M. Groen by Eli Lilly, J and H. The University of Leiden: money for P. S. Hiemstra regarding an unrestricted educational grant for research from D, Galapagos. The University of Amsterdam: a public-private grant for P. S. Sterk by Innovative Medicine Initiative by European Union and European Federation of Pharmaceutical Industries and Associations. Boston University Medical Center holds patents. A. Spira: money for board membership, consultancy, and stock options from Allegro Diagnostics, Inc. Money for consultancy and for lectures was paid to J. Vestbo by E, F, B, Syntaxin, Bioxydyn, Novartis, A, and D. University Hospital of Heidelberg: money for expert testimony for H.U.Kauczor. H. U. Kauczor: money for board membership from I, for lectures from Bracco, I, D, and Bayer, and for development of educational presentations from I. The Jagiellonian University Medical College of Krakow: a Grant (Z/7PR/00010,201 379) for E. Nizankowska-Mogilnicka. E. Silverman: a grant for Harvard University from E. E. Silverman: consulting fee and support for travel to meetings for the study or other purposes (COPDGene and ECLIPSE) from E and the COPD foundation and money for consultancy and lectures from E, A and C. M. Cho: NIH/NHLBI grants (K12HL089990 and K08 HL097029) for Harvard University and money for consultancy from C. Erasmus Medical Center Rotterdam: a grant for H. de Koning from ZonMw, KWF, Kankerbestrijding, Stichting Centraal Fonds Reseves van Voormalig Vrijwillige Ziekenfondsverzekeringen; H provided a grant for the performance of proteomics research, and I provided 4-digital workstations for LungCare for the performance of 3Dmeasurements. Johns Hopkins Bloomberg School of Public Health in Baltimore: a NIH grant for J. Crapo. The National Jewish Health Center in Denver: a grant for T. Beaty from the National Institutes of Health and National Institute Heart, Lung & Blood Disease. T. Beaty: money for travel support by the COPD foundation. University of Cambridge: a grant for D. Lomas from E. D. Lomas: money for board membership, consultancy, lectures, and travel accommodations from E, Talecris/Grifols, and D. P. Bakke: money for lectures from E, A, and J. L. Lahousse: a travel award for the ATS (2012) and a short-term Research Fellowship for transport to Rotterdam. Part of the GLUCOLD study was supported by GlaxoSmithKline, the ECLIPSE study was partly funded by GSK, and the COPDGene study was partly funded by the COPD foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovion. Data sampling for the Norway study was funded by GlaxoSmithKline. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. Patent nr. subjectdate 1US 2013/0023437Diagnostic for lung disorders using class prediction 2012-06-15 2US 2012/0322673Isolation of nucleic acid from mouth epithelial cells 2012-03-23 3US 2012/0190567Diagnostic and prognostic methods for lung disorders using gene expression profiles from nose epithelial cells 2011-12-12 4US 2011/0217717Diagnostic and prognostic methods for lung disorders using gene expression profiles from nose epithelial cells2010-11-05 5US 2011/0190150Isolation of nucleic acid from mouth epithelial cells 2010-09-17 6US 2012/0041686Diagnostic for lung disorders using class prediction 2010-08-26 7US 2010/0055689Multifactorial methods for detecting lung disorders2009-03-30 8US 2009/0311692Isolation of nucleic acid from mouth epithelial cells 2009-01-09 9US 2009/0186951Identification of novel pathways for drug development for lung disease 2008-09-19 10US 2009/0061454Diagnostic and prognostic methods for lung disorders using gene expression profiles from nose epithelial cells 2007-03-08 11 US 2010/0035244Diagnostic for lung disorders using class prediction2006-04-14 12US 2006/0154278Detection methods for disorders of the lung2005-12-06 13US 2007/0148650Isolation of nucleic acid from mouth epithelial cells2004-11-12.

Figures

**Figure 1. Study design.**
We performed GWA studies in the NELSON cohort and in additional healthy controls. CMH was analyzed using logistic regression with adjustment for center (Groningen and Utrecht). Since current smoking can affect the presence of CMH, we additionally performed the GWAS in the NELSON cohort correcting for center and smoking. SNPs with a p-value<10-4 present in both GWA studies were selected for replication. To test for generalizability of associations with CMH in other populations, we compared our results with data in CMH-cases and controls with a smoking history of ≥20 pack-years with eleven replication populations using logistic regression with adjustment for sex and current smoking. Finally, we performed a meta-analysis on shared SNPs across the NELSON identification population and the 11 replication populations.

**Figure 2. Quantile-quantile plot and Manhattan plot of GWA results for association of SNPs with CMH in NELSON amplified with bloodbank controls and corrected for center (A and B).**
Quantile-quantile plot and Manhattan plot of GWA results for association of SNPs with CMH in NELSON, corrected for center and smoking habits (C and D).

**Figure 3. Forest plot showing evidence of association for rs6577641 with chronic mucus hypersecretion in the identification and replication cohorts.**
Vertically left, the identification cohort and the replication cohorts included in the meta-analysis. The boxes represent the precision and the horizontal lines represent the confidence intervals. The squares represent the pooled effect estimate from the meta-analysis of all cohorts. The horizontal axis shows the scale of the effects.

Figure 4. Percentage of subjects with chronic mucus hypersecretion (CMH) within genotypes (AA, AG and GG) of rs6577641 in the identification cohort (NELSON), and distributed among ex- and current smokers.

**Figure 5. Bronchial biopsy mRNA-expression levels of SATB1 in COPD patients with chronic mucus hypersecretion (n = 38) compared to patients without chronic mucus hypersecretion (n = 39).**

**Figure 6. *SATB1*, *MUC5AC* and *FOXJ1* mRNA expression levels during mucociliary human airway epithelial cell differentiation (n = 2 donors).**
Expression of *SATB1*, the identified gene in our study, *MUC5AC* a marker of mucus, and *FOXJ1*, representing ciliated cells in epithelial cell culture on air liquid interface.

See this image and copyright information in PMC

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Susceptibility to chronic mucus hypersecretion, a genome wide association study

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Susceptibility to chronic mucus hypersecretion, a genome wide association study

Authors

Collaborators

Affiliations

Erratum in

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Conflict of interest statement

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