Susceptibility to chronic mucus hypersecretion, a genome wide association study.
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.
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.
Akkelies E
AE
Dijkstra
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.
Joanna
J
Smolonska
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.
Maarten
M
van den Berge
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
Ciska
C
Wijmenga
University of Utrecht, University Medical Center Utrecht, Department of Pulmonology, Utrecht, the Netherlands.
Pieter
P
Zanen
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
Marjan A
MA
Luinge
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
Mathieu
M
Platteel
University of Utrecht, University Medical Center Utrecht, Department of Pulmonology, Utrecht, the Netherlands.
Jan-Willem
JW
Lammers
AstraZeneca, R&D Mölndal, Mölndal, Sweden.
Magnus
M
Dahlback
AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Kerrie
K
Tosh
Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands.
Pieter S
PS
Hiemstra
Department of Respiratory Medicine, University of Amsterdam, Amsterdam, the Netherlands.
Peter J
PJ
Sterk
Department of Medicine, Section of Computational Biomedicine, Boston University Medical Center, Boston, Massachusetts, United States of America.
Avi
A
Spira
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.
Jorgen
J
Vestbo
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.
Borge G
BG
Nordestgaard
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
Marianne
M
Benn
The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
Sune F
SF
Nielsen
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
Morten
M
Dahl
Center for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
W Monique
WM
Verschuren
Center for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
H Susan J
HS
Picavet
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, the Netherlands.
Henriette A
HA
Smit
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.
Michael
M
Owsijewitsch
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.
Hans U
HU
Kauczor
Department of Public Health, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.
Harry J
HJ
de Koning
Department of Respiratory Diseases, Jagiellonian University Medical College, Krakow, Poland.
Eva
E
Nizankowska-Mogilnicka
Department of Respiratory Diseases, Jagiellonian University Medical College, Krakow, Poland.
Filip
F
Mejza
Department of Respiratory Diseases, Jagiellonian University Medical College, Krakow, Poland.
Pawel
P
Nastalek
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
Cleo C
CC
van Diemen
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.
Michael H
MH
Cho
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.
Edwin K
EK
Silverman
Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado, United States of America.
James D
JD
Crapo
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Terri H
TH
Beaty
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
David A
DA
Lomas
Department of Thoracic Medicine, Haukeland University, Hospital and Institute of Medicine, University of Bergen, Bergen, Norway.
Per
P
Bakke
Department of Thoracic Medicine, Haukeland University, Hospital and Institute of Medicine, University of Bergen, Bergen, Norway.
Amund
A
Gulsvik
Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec City, Canada.
Yohan
Y
Bossé
Ma'en
M
Obeidat
Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
M A
MA
Obeidat
Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; The Netherlands Healthcare Inspectorate, The Hague, the Netherlands.
Daan W
DW
Loth
Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of respiratory medicine, University Hospital Ghent, Ghent, Belgium.
Lies
L
Lahousse
Department of Internal medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
Fernando
F
Rivadeneira
Department of Internal medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
Andre G
AG
Uitterlinden
Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
Andre
A
Hofman
Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; The Netherlands Healthcare Inspectorate, The Hague, the Netherlands.
Bruno H
BH
Stricker
Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of respiratory medicine, University Hospital Ghent, Ghent, Belgium.
Guy G
GG
Brusselle
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.
Cornelia M
CM
van Duijn
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.
Uilke
U
Brouwer
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.
Gerard H
GH
Koppelman
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.
Judith M
JM
Vonk
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.
Martijn C
MC
Nawijn
University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, the Netherlands.
Harry J M
HJ
Groen
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
Wim
W
Timens
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.
H Marike
HM
Boezen
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.
Dirkje S
DS
Postma
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics*; D008875:Middle Aged; D009093:Mucus / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*
D036961:Matrix Attachment Region Binding Proteins; C076189:SATB1 protein, human