Dijkstra, Akkelies E2; Smolonska, Joanna2; van den Berge, Maarten2; Wijmenga, Ciska2; Zanen, Pieter2; Luinge, Marjan A2; Platteel, Mathieu2; Lammers, Jan-Willem2; Dahlback, Magnus2; Tosh, Kerrie2; Hiemstra, Pieter S2; Sterk, Peter J2; Spira, Avi2; Vestbo, Jorgen2; Nordestgaard, Børge3; Benn, Marianne3; Nielsen, Sune F2; Dahl, Morten2; Verschuren, W Monique2; Picavet, H Susan J2; Smit, Henriette A2; Owsijewitsch, Michael2; Kauczor, Hans U2; de Koning, Harry J2; Nizankowska-Mogilnicka, Eva2; Mejza, Filip2; Nastalek, Pawel2; van Diemen, Cleo C2; Cho, Michael H2; Silverman, Edwin K2; Crapo, James D2; Beaty, Terri H2; Lomas, David A2; Bakke, Per2; Gulsvik, Amund2; Bossé, Yohan2; Obeidat, M A2; Loth, Daan W2; Lahousse, Lies2; Rivadeneira, Fernando2; Uitterlinden, Andre G2; Hofman, Andre2; Stricker, Bruno H2; Brusselle, Guy G2; van Duijn, Cornelia M2; Brouwer, Uilke2; Koppelman, Gerard H2; Vonk, Judith M2; Nawijn, Martijn C2; Groen, Harry J M2; Timens, Wim2; Boezen, H Marike2; Postma, Dirkje S2
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.