TY - JOUR
T1 - Susceptibility to chronic mucus hypersecretion, a genome wide association study
AU - Dijkstra, Akkelies E.
AU - Smolonska, Joanna
AU - van den Berge, Maarten
AU - Wijmenga, Cisca
AU - Zanen, Pieter
AU - Luinge, Marjan A.
AU - Platteel, Mathieu
AU - Lammers, Jan-Willem
AU - Dahlback, Magnus
AU - Tosh, Kerrie
AU - Hiemstra, Pieter S.
AU - Sterk, Peter J.
AU - Spira, Avi
AU - Vestbo, Jorgen
AU - Nordestgaard, Borge G.
AU - Benn, Marianne
AU - Nielsen, Sune F.
AU - Dahl, Morten
AU - Verschuren, W. Monique
AU - Picavet, H. Susan J.
AU - Smit, Henriette A.
AU - Owsijewitsch, Michael
AU - Kauczor, Hans U.
AU - de Koning, Harry J.
AU - Nizankowska-Mogilnicka, Eva
AU - Mejza, Filip
AU - Nastalek, Pawel
AU - van Diemen, Cleo C.
AU - Cho, Michael H.
AU - Silverman, Edwin K.
AU - Crapo, James D.
AU - Beaty, Terri H.
AU - Lomas, David A.
AU - Bakke, Per
AU - Gulsvik, Amund
AU - Bosse, Yohan
AU - Obeidat, M. A.
AU - Loth, Daan W.
AU - Lahousse, Lies
AU - Rivadeneira, Fernando
AU - Uitterlinden, Andre G.
AU - Hofman, Andre
AU - Brouwer, Uilke
AU - Koppelman, Gerard H.
AU - Vonk, Judith M.
AU - Nawijn, Martijn C.
AU - Groen, Harry J.M.
AU - Timens, Wim
AU - Boezen, Hendrika
AU - Postma, Dirkje S.
AU - Lifelines Cohort Study
PY - 2014/4/8
Y1 - 2014/4/8
N2 - 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 metaanalysis 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 = 4.25610(-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 (4.3610 29) 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.
AB - 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 metaanalysis 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 = 4.25610(-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 (4.3610 29) 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.
KW - OBSTRUCTIVE PULMONARY-DISEASE
KW - CHRONIC-BRONCHITIS
KW - GENETIC EPIDEMIOLOGY
KW - GENERAL-POPULATION
KW - BINDING-PROTEIN
KW - RISK-FACTORS
KW - COPD
KW - CHROMATIN
KW - SATB1
KW - EXPRESSION
U2 - 10.1371/journal.pone.0091621
DO - 10.1371/journal.pone.0091621
M3 - Article
C2 - 24714607
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e91621
ER -