2015
Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD
Publication
Publication
The European Respiratory Journal , Volume 45 - Issue 1 p. 60- 75
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.
| Additional Metadata | |
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| doi.org/10.1183/09031936.00093314, hdl.handle.net/1765/81631 | |
| The European Respiratory Journal | |
| Organisation | Department of Public Health |
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Dijkstra, A., Boezen, M., van den Berge, M., Vonk, J., Hiemstra, P., Barr, G., … Wijmenga, C. (2015). Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD. The European Respiratory Journal, 45(1), 60–75. doi:10.1183/09031936.00093314 |
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