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1. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), Cho, M.H. (Michael), Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), and Cho, M.H. (Michael)

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017
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2. Susceptibility to chronic mucus hypersecretion, a genome wide association study

Author

Dijkstra, A.E. (Akkelies), Smolonska, J. (Joanna), Berge, M. (Maarten) van den, Wijmenga, C. (Ciska), Zanen, P. (Pieter), Luinge, M.A. (Marjan), Platteel, I. (Inge), Lammers, J.-W.J. (Jan-Willem), Dahlback, M. (Magnus), Tosh, K. (Kerrie), Hiemstra, P.S. (Pieter), Sterk, P.J. (Peter), Spira, M.E. (Micha), Vestbo, J. (Jorgen), Nordestgaard, B.G. (Børge), Benn, M. (Marianne), Nielsen, S.F. (Sune), Dahl, M. (Morten), Verschuren, W.M.M. (W. M. Monique), Picavet, H.S.J. (Susan), Smit, H.A. (Henriëtte), Owsijewitsch, M. (Michael), Kauczor, H.U. (Hans), Koning, H.J. (Harry) de, Nizankowska-Mogilnicka, E. (Eva), Mejza, F. (Filip), Nastalek, P. (Pawel), Diemen, C.C. (Cleo) van, Cho, M.H. (Michael), Silverman, E.K. (Edwin), Crapo, R.O. (Robert), Beaty, T.H. (Terri), Lomas, D.J. (David John), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Bossé, Y. (Yohan), Obeidat, M. (Ma'en), Loth, D.W. (Daan), Lahousse, L. (Lies), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Duijn, C.M. (Cornelia) van, Brouwer, U. (Uilke), Koppelman, G.H. (Gerard), Vonk, J.M. (Judith), Nawijn, M.C. (Martijn), Groen, H.J.M. (Henk), Timens, W. (Wim), Boezen, H.M. (Marike), Postma, D.S. (Dirkje), Alizadeh, B.Z. (Behrooz), Boer, R.A. (Rudolf) de, Bruinenberg, M. (M.), Franke, L. (Lude), Harst, P. (Pim) van der, Hillege, H.L. (Hans), Klauw, M.M. (Melanie) van der, Navis, G. (Gerjan), Ormel, J. (Johan), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Snieder, H. (Harold), Stolk, R.P. (Ronald), Wolffenbuttel, B. (Bhr), Dijkstra, A.E. (Akkelies), Smolonska, J. (Joanna), Berge, M. (Maarten) van den, Wijmenga, C. (Ciska), Zanen, P. (Pieter), Luinge, M.A. (Marjan), Platteel, I. (Inge), Lammers, J.-W.J. (Jan-Willem), Dahlback, M. (Magnus), Tosh, K. (Kerrie), Hiemstra, P.S. (Pieter), Sterk, P.J. (Peter), Spira, M.E. (Micha), Vestbo, J. (Jorgen), Nordestgaard, B.G. (Børge), Benn, M. (Marianne), Nielsen, S.F. (Sune), Dahl, M. (Morten), Verschuren, W.M.M. (W. M. Monique), Picavet, H.S.J. (Susan), Smit, H.A. (Henriëtte), Owsijewitsch, M. (Michael), Kauczor, H.U. (Hans), Koning, H.J. (Harry) de, Nizankowska-Mogilnicka, E. (Eva), Mejza, F. (Filip), Nastalek, P. (Pawel), Diemen, C.C. (Cleo) van, Cho, M.H. (Michael), Silverman, E.K. (Edwin), Crapo, R.O. (Robert), Beaty, T.H. (Terri), Lomas, D.J. (David John), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Bossé, Y. (Yohan), Obeidat, M. (Ma'en), Loth, D.W. (Daan), Lahousse, L. (Lies), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Duijn, C.M. (Cornelia) van, Brouwer, U. (Uilke), Koppelman, G.H. (Gerard), Vonk, J.M. (Judith), Nawijn, M.C. (Martijn), Groen, H.J.M. (Henk), Timens, W. (Wim), Boezen, H.M. (Marike), Postma, D.S. (Dirkje), Alizadeh, B.Z. (Behrooz), Boer, R.A. (Rudolf) de, Bruinenberg, M. (M.), Franke, L. (Lude), Harst, P. (Pim) van der, Hillege, H.L. (Hans), Klauw, M.M. (Melanie) van der, Navis, G. (Gerjan), Ormel, J. (Johan), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Snieder, H. (Harold), Stolk, R.P. (Ronald), and Wolffenbuttel, B. (Bhr)

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.

Published
2014
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