Susceptibility to chronic mucus hypersecretion, a genome wide association study

Akkelies E. Dijkstra, Joanna Smolonska, Maarten van den Berge, Cisca 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 Bosse, M. A. Obeidat, Daan W. Loth, Lies Lahousse, Fernando Rivadeneira, Andre G. Uitterlinden, Andre Hofman, Uilke Brouwer, Gerard H. Koppelman, Judith M. Vonk, Martijn C. Nawijn, Harry J.M. Groen, Wim Timens, Hendrika Boezen, Dirkje S. Postma*, Lifelines Cohort Study

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article numbere91621
Number of pages13
JournalPLoS ONE
Issue number4
Publication statusPublished - 8-Apr-2014


  • COPD
  • SATB1

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