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Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Author

Listed:
  • 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
  • the LifeLines Cohort 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 = 4.25×10−6, 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 (4.3×10−9) 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.

Suggested Citation

  • 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 Hiem, 2014. "Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study," PLOS ONE, Public Library of Science, vol. 9(4), pages 1-13, April.
  • Handle: RePEc:plo:pone00:0091621
    DOI: 10.1371/journal.pone.0091621
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    References listed on IDEAS

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    1. Ke Hao & Yohan Bossé & David C Nickle & Peter D Paré & Dirkje S Postma & Michel Laviolette & Andrew Sandford & Tillie L Hackett & Denise Daley & James C Hogg & W Mark Elliott & Christian Couture & Max, 2012. "Lung eQTLs to Help Reveal the Molecular Underpinnings of Asthma," PLOS Genetics, Public Library of Science, vol. 8(11), pages 1-11, November.
    2. Dag Yasui & Masaru Miyano & Shutao Cai & Patrick Varga-Weisz & Terumi Kohwi-Shigematsu, 2002. "SATB1 targets chromatin remodelling to regulate genes over long distances," Nature, Nature, vol. 419(6907), pages 641-645, October.
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