Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD
Dijkstra, Akkelies E.; Boezen, H. Marike; Van Den Berge, Maarten; Vonk, Judith M.; Hiemstra, Pieter S.; Barr, R. Graham; Burkart, Kirsten M.; Manichaikul, Ani; Pottinger, Tess D.; Silverman, Edward K.; Cho, Michael H.; Crapo, James D.; Beaty, Terri H.; Bakke, Per; Gulsvik, Amund; Lomas, David A.; Bossé, Yohan; Nickle, David C.; Paré, Peter D.; De Koning, Harry J.; Lammers, Jan Willem; Zanen, Pieter; Smolonska, Joanna; Wijmenga, Ciska; Brandsma, Corry Anke; Groen, Harry J M; Postma, Dirkje S.; Alizadeh, B. Z.; De Boer, R. A.; Boezen, H. M.; Bruinenberg, M.; Franke, L.; Van Der Harst, P.; Hillege, H. L.; Van Der Klauw, M. M.; Navis, G.; Ormel, J.; Postma, D. S.; Rosmalen, J. G M; Slaets, J. P.; Snieder, H.; Stolk, R. P.; Wolffenbuttel, B. H R; Wijmenga, C.
(2015) European Respiratory Journal, volume 45, issue 1, pp. 60 - 75
(Article)
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
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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.
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Keywords: Pulmonary and Respiratory Medicine
ISSN: 0903-1936
Publisher: European Respiratory Society
(Peer reviewed)