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Eur Respir J. 2015 Jan;45(1):60-75. doi: 10.1183/09031936.00093314. Epub 2014 Sep 18.

Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.

Author information

1
For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section d.s.postma@umcg.nl.
2
For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.

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.

PMID:
25234806
PMCID:
PMC4498483
DOI:
10.1183/09031936.00093314
[Indexed for MEDLINE]
Free PMC Article

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