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; Borge G. 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; Wim Timens; H. Marike Boezen; Dirkje S. Postma; B. Z. Alizadeh; R. A. De Boer; M. Bruinenberg; L. Franke; P. Van Der Harst; H. L. Hillege; M. M. Van Der Klauw; G. Navis; J. Ormel; Jgm Rosmalen; J. P. Slaets; H. Snieder; R. P. Stolk; Bhr Wolffenbuttel

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, Borge G. 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, Wim Timens, H. Marike Boezen, Dirkje S. Postma, B. Z. Alizadeh, R. A. De Boer, M. Bruinenberg, L. Franke, P. Van Der Harst, H. L. Hillege, M. M. Van Der Klauw, G. Navis, J. Ormel, Jgm Rosmalen, J. P. Slaets, H. Snieder, R. P. Stolk, Bhr Wolffenbuttel

Research output: Contribution to journal › Article › peer-review

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. © 2014 Dijkstra et al.

Original language	English
Article number	e91621
Journal	PLoS ONE
Volume	9
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0091621
Publication status	Published - 8 Apr 2014

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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. G., Benn, M., Nielsen, S. F., Dahl, M., Verschuren, W. M., ... Wolffenbuttel, B. (2014). Susceptibility to chronic mucus hypersecretion, a genome wide association study. PLoS ONE, 9(4), Article e91621. https://doi.org/10.1371/journal.pone.0091621

@article{ee82a3e69c8c467782c0da94fffa47e4,

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. {\textcopyright} 2014 Dijkstra et al.",

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 Lammers, {Jan Willem} and Magnus Dahlback and Kerrie Tosh and Hiemstra, {Pieter S.} and Sterk, {Peter J.} and Avi Spira and Jorgen Vestbo and Nordestgaard, {Borge G.} 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 Wim Timens and Boezen, {H. Marike} and Postma, {Dirkje S.} and Alizadeh, {B. Z.} and {De Boer}, {R. A.} and M. Bruinenberg and L. Franke and {Van Der Harst}, P. and Hillege, {H. L.} and {Van Der Klauw}, {M. M.} and G. Navis and J. Ormel and Jgm Rosmalen and Slaets, {J. P.} and H. Snieder and Stolk, {R. P.} and Bhr Wolffenbuttel",

note = "R0 I HL089856, NHLBI NIH HHS, United StatesR0 I HL089897, NHLBI NIH HHS, United States",

year = "2014",

month = apr,

day = "8",

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

language = "English",

volume = "9",

journal = "PLoS ONE",

publisher = "Public Library of Science",

number = "4",

}

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, 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, Timens, W, Boezen, HM, Postma, DS, Alizadeh, BZ, De Boer, RA, Bruinenberg, M, Franke, L, Van Der Harst, P, Hillege, HL, Van Der Klauw, MM, Navis, G, Ormel, J, Rosmalen, J, Slaets, JP, Snieder, H, Stolk, RP & Wolffenbuttel, B 2014, 'Susceptibility to chronic mucus hypersecretion, a genome wide association study', PLoS ONE, vol. 9, no. 4, e91621. https://doi.org/10.1371/journal.pone.0091621

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, 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 - 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 - Timens, Wim

AU - Boezen, H. Marike

AU - Postma, Dirkje S.

AU - Alizadeh, B. Z.

AU - De Boer, R. A.

AU - Bruinenberg, M.

AU - Franke, L.

AU - Van Der Harst, P.

AU - Hillege, H. L.

AU - Van Der Klauw, M. M.

AU - Navis, G.

AU - Ormel, J.

AU - Rosmalen, Jgm

AU - Slaets, J. P.

AU - Snieder, H.

AU - Stolk, R. P.

AU - Wolffenbuttel, Bhr

N1 - R0 I HL089856, NHLBI NIH HHS, United StatesR0 I HL089897, NHLBI NIH HHS, United States

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. © 2014 Dijkstra et al.

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. © 2014 Dijkstra et al.

U2 - 10.1371/journal.pone.0091621

DO - 10.1371/journal.pone.0091621

M3 - Article

C2 - 24714607

VL - 9

JO - PLoS ONE

JF - PLoS ONE

IS - 4

M1 - e91621

ER -

Susceptibility to chronic mucus hypersecretion, a genome wide association study

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