@article {Dijkstra60, author = {Akkelies E. Dijkstra and H. Marike Boezen and Maarten van den Berge and Judith M. Vonk and Pieter S. Hiemstra and R. Graham Barr and Kirsten M. Burkart and Ani Manichaikul and Tess D. Pottinger and Edward K. Silverman and Michael H. Cho and James D. Crapo and Terri H. Beaty and Per Bakke and Amund Gulsvik and David A. Lomas and Yohan Boss{\'e} and David C. Nickle and Peter D. Par{\'e} and Harry J. de Koning and Jan-Willem Lammers and Pieter Zanen and Joanna Smolonska and Ciska Wijmenga and Corry-Anke Brandsma and Harry J.M. Groen and Dirkje S. Postma and the LifeLines Cohort Study group}, title = {Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD}, volume = {45}, number = {1}, pages = {60--75}, year = {2015}, doi = {10.1183/09031936.00093314}, publisher = {European Respiratory Society}, 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{\texttimes}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{\texttimes}10-6, OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59{\texttimes}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}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/45/1/60}, eprint = {https://erj.ersjournals.com/content/45/1/60.full.pdf}, journal = {European Respiratory Journal} }