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

Akkelies E Dijkstra, Hendrika Boezen, Maarten van den Berge, Judith M Vonk, Pieter S Hiemstra, R Graham Barr, Kirsten M Burkart, Ani Manichaikul, Tess D Pottinger, Edward K Silverman, Michael H Cho, James D Crapo, Terri H Beaty, Per Bakke, Amund Gulsvik, David A Lomas, Yohan Bossé, David C Nickle, Peter D Paré, Harry J de KoningJan-Willem Lammers, Pieter Zanen, Joanna Smolonska, Cisca Wijmenga, Corry-Anke Brandsma, Harry J.M. Groen, Dirkje S Postma, the LifeLines Cohort Study group

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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.

Original languageEnglish
Pages (from-to)60-75
Number of pages16
JournalEuropean Respiratory Journal
Issue number1
Publication statusPublished - Jan-2015



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