PT  - JOURNAL ARTICLE
AU  - Akkelies E. Dijkstra
AU  - H. Marike Boezen
AU  - Maarten van den Berge
AU  - Judith M. Vonk
AU  - Pieter S. Hiemstra
AU  - R. Graham Barr
AU  - Kirsten M. Burkart
AU  - Ani Manichaikul
AU  - Tess D. Pottinger
AU  - Edward K. Silverman
AU  - Michael H. Cho
AU  - James D. Crapo
AU  - Terri H. Beaty
AU  - Per Bakke
AU  - Amund Gulsvik
AU  - David A. Lomas
AU  - Yohan Bossé
AU  - David C. Nickle
AU  - Peter D. Paré
AU  - Harry J. de Koning
AU  - Jan-Willem Lammers
AU  - Pieter Zanen
AU  - Joanna Smolonska
AU  - Ciska Wijmenga
AU  - Corry-Anke Brandsma
AU  - Harry J.M. Groen
AU  - Dirkje S. Postma
AU  - the LifeLines Cohort Study group
TI  - Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD
AID  - 10.1183/09031936.00093314
DP  - 2015 Jan 01
TA  - European Respiratory Journal
PG  - 60--75
VI  - 45
IP  - 1
4099  - http://erj.ersjournals.com/content/45/1/60.short
4100  - http://erj.ersjournals.com/content/45/1/60.full
SO  - Eur Respir J2015 Jan 01; 45
AB  - 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. Genetic determinants of chronic mucus hypersecretion may differ by COPD status http://ow.ly/AeqCr