Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Akkelies E Dijkstra; Joanna Smolonska; Maarten van den Berge; Ciska Wijmenga; Pieter Zanen; Marjan A Luinge; Mathieu Platteel; Jan-Willem Lammers; Magnus Dahlback; Kerrie Tosh; Pieter S Hiemstra; Peter J Sterk; Avi Spira; Jorgen Vestbo; Børge Nordestgaard; Marianne Benn; Sune F Nielsen; Morten Dahl; W Monique Verschuren; H Susan J Picavet; Henriette A Smit; Michael Owsijewitsch; Hans U Kauczor; Harry J de Koning; Eva Nizankowska-Mogilnicka; Filip Mejza; Pawel Nastalek; Cleo C van Diemen; Michael H Cho; Edwin K Silverman; James D Crapo; Terri H Beaty; David A Lomas; Per Bakke; Amund Gulsvik; Yohan Bossé; M A Obeidat; Daan W Loth; Lies Lahousse; Fernando Rivadeneira; Andre G Uitterlinden; Andre Hofman; Bruno H Stricker; Guy G Brusselle; Cornelia M van Duijn; Uilke Brouwer; Gerard H Koppelman; Judith M Vonk; Martijn C Nawijn; Harry J M Groen; LifeLines Cohort study

doi:10.1371/journal.pone.0091621

Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Akkelies E Dijkstra, Joanna Smolonska, Maarten van den Berge, Ciska Wijmenga, Pieter Zanen, Marjan A Luinge, Mathieu Platteel, Jan-Willem Lammers, Magnus Dahlback, Kerrie Tosh, Pieter S Hiemstra, Peter J Sterk, Avi Spira, Jorgen Vestbo, Børge Nordestgaard, Marianne Benn, Sune F Nielsen, Morten Dahl, W Monique Verschuren, H Susan J PicavetHenriette A Smit, Michael Owsijewitsch, Hans U Kauczor, Harry J de Koning, Eva Nizankowska-Mogilnicka, Filip Mejza, Pawel Nastalek, Cleo C van Diemen, Michael H Cho, Edwin K Silverman, James D Crapo, Terri H Beaty, David A Lomas, Per Bakke, Amund Gulsvik, Yohan Bossé, M A Obeidat, Daan W Loth, Lies Lahousse, Fernando Rivadeneira, Andre G Uitterlinden, Andre Hofman, Bruno H Stricker, Guy G Brusselle, Cornelia M van Duijn, Uilke Brouwer, Gerard H Koppelman, Judith M Vonk, Martijn C Nawijn, Harry J M Groen, LifeLines Cohort study

Institut for Klinisk Medicin

19 Citationer (Scopus)

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 = 4.25x10^-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 (4.3x10 ^-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.

Originalsprog	Engelsk
Artikelnummer	e91621
Tidsskrift	PLOS ONE
Vol/bind	9
Udgave nummer	4
Sider (fra-til)	1-13
Antal sider	13
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0091621
Status	Udgivet - 8 apr. 2014

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10.1371/journal.pone.0091621

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Dijkstra, A. E., Smolonska, J., van den Berge, M., Wijmenga, C., Zanen, P., Luinge, M. A., Platteel, M., Lammers, J-W., Dahlback, M., Tosh, K., Hiemstra, P. S., Sterk, P. J., Spira, A., Vestbo, J., Nordestgaard, B., Benn, M., Nielsen, S. F., Dahl, M., Verschuren, W. M., ... LifeLines Cohort study (2014). Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study. PLOS ONE, 9(4), 1-13. [e91621]. https://doi.org/10.1371/journal.pone.0091621

Dijkstra, AE, Smolonska, J, van den Berge, M, Wijmenga, C, Zanen, P, Luinge, MA, Platteel, M, Lammers, J-W, Dahlback, M, Tosh, K, Hiemstra, PS, Sterk, PJ, Spira, A, Vestbo, J, Nordestgaard, B , Benn, M, Nielsen, SF, Dahl, M, Verschuren, WM, Picavet, HSJ, 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, MA, 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, HJM & LifeLines Cohort study 2014, 'Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study', PLOS ONE, bind 9, nr. 4, e91621, s. 1-13. https://doi.org/10.1371/journal.pone.0091621

@article{20dad9c4f86d47ed9930d515f835b1fe,

title = "Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study",

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 = 4.25x10-6, 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 (4.3x10 -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.",

keywords = "Adult, Aged, Aged, 80 and over, Cells, Cultured, Chronic Disease, Cohort Studies, Female, Genome-Wide Association Study, Humans, Lung, Male, Matrix Attachment Region Binding Proteins, Middle Aged, Mucus, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive",

author = "Dijkstra, {Akkelies E} and Joanna Smolonska and {van den Berge}, Maarten and Ciska Wijmenga and Pieter Zanen and Luinge, {Marjan A} and Mathieu Platteel and Jan-Willem Lammers and Magnus Dahlback and Kerrie Tosh and Hiemstra, {Pieter S} and Sterk, {Peter J} and Avi Spira and Jorgen Vestbo and B{\o}rge Nordestgaard and Marianne Benn and Nielsen, {Sune F} and Morten Dahl and Verschuren, {W Monique} and Picavet, {H Susan J} and Smit, {Henriette A} and Michael Owsijewitsch and Kauczor, {Hans U} and {de Koning}, {Harry J} and Eva Nizankowska-Mogilnicka and Filip Mejza and Pawel Nastalek and {van Diemen}, {Cleo C} and Cho, {Michael H} and Silverman, {Edwin K} and Crapo, {James D} and Beaty, {Terri H} and Lomas, {David A} and Per Bakke and Amund Gulsvik and Yohan Boss{\'e} and Obeidat, {M A} and Loth, {Daan W} and Lies Lahousse and Fernando Rivadeneira and Uitterlinden, {Andre G} and Andre Hofman and Stricker, {Bruno H} and Brusselle, {Guy G} and {van Duijn}, {Cornelia M} and Uilke Brouwer and Koppelman, {Gerard H} and Vonk, {Judith M} and Nawijn, {Martijn C} and Groen, {Harry J M} and {LifeLines Cohort study}",

year = "2014",

month = apr,

day = "8",

doi = "10.1371/journal.pone.0091621",

language = "English",

volume = "9",

pages = "1--13",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "4",

}

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, Ciska

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, Børge

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 - Bossé, Yohan

AU - Obeidat, M A

AU - Loth, Daan W

AU - Lahousse, Lies

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G

AU - Hofman, Andre

AU - Stricker, Bruno H

AU - Brusselle, Guy G

AU - van Duijn, Cornelia M

AU - Brouwer, Uilke

AU - Koppelman, Gerard H

AU - Vonk, Judith M

AU - Nawijn, Martijn C

AU - Groen, Harry J M

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 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 = 4.25x10-6, 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 (4.3x10 -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.

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 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 = 4.25x10-6, 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 (4.3x10 -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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Cells, Cultured

KW - Chronic Disease

KW - Cohort Studies

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Lung

KW - Male

KW - Matrix Attachment Region Binding Proteins

KW - Middle Aged

KW - Mucus

KW - Polymorphism, Single Nucleotide

KW - Pulmonary Disease, Chronic Obstructive

U2 - 10.1371/journal.pone.0091621

DO - 10.1371/journal.pone.0091621

M3 - Journal article

C2 - 24714607

SN - 1932-6203

VL - 9

SP - 1

EP - 13

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 4

M1 - e91621

ER -

Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

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