Abstract
Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD.
We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs.
Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10−5) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value <10−5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10−6, OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10−12).
Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.
Abstract
Genetic determinants of chronic mucus hypersecretion may differ by COPD status http://ow.ly/AeqCr
Footnotes
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Support statement: The COPACETIC study was funded by European Union (EU) Seventh Framework grant 201379. The NELSON study was supported by Zorg Onderzoek Nederland-Medische Wetenschappen, KWF Kankerbestrijiding, and Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen. The LifeLines Cohort Study was sponsored by the Dutch ministry of Health, Welfare and Sport, the Ministry of Economic Affairs, Agriculture and Innovation, the Province of Groningen, the EU Regional Development Fund, the Northern Netherlands Provinces (SNN), the Netherlands Organisation for Scientific Research (NWO), University Medical Center Groningen, University of Groningen, de Nierstichting (the Dutch Kidney Foundation) and the Diabetes Fonds (the Diabetic Foundation). The COPDGene study was funded by US National Institutes of Health (NIH) grants R01 HL089856 and R01 HL089897, and by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovion. The ECLIPSE study was funded by GlaxoSmithKline. Data sampling for the GenKOLS study was funded by GlaxoSmithKline. The MESA Lung/SHARe Study was funded by NIH grant RC1HL100543. MESA and the MESA SHARe project are conducted and supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the National Heart, Lung, and Blood Institute (NHLBI). MESA Air is conducted and supported by the US Environmental Protection Agency in collaboration with the MESA Air investigators, with support provided by grant RD83169701. Funding for MESA SHARe genotyping was provided by NHLBI contract N02-HL-6-4278. MESA Family is conducted and supported in collaboration with the MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259, M01-RR00425, UL1RR033176 and UL1TR000124. The MESA Lung and MESA COPD Studies are funded by NIH grants R01HL077612 and R01HL093081. A full list of participating MESA investigators and institutions can be found at www.mesa-nhlbi.org. The lung eQTL study at Laval University was supported by the Chaire de Pneumologie de la Fondation J.D. Bégin de l’Université Laval, the Fondation de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, the Respiratory Health Network of the Fonds de Recherche Québec – Santé (FRQS), the Canadian Institutes of Health Research (MOP - 123369), the Cancer Research Society, and Read for the Cure. Y. Bossé is the recipient of a Junior 2 Research Scholar award from the FRQS.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received May 21, 2014.
- Accepted August 4, 2014.
- Copyright ©ERS 2015