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

Akkelies E. Dijkstra, H. Marike 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, Ciska Wijmenga, Corry Anke Brandsma, Harry J.M. Groen, Dirkje S. Postma, B. Z. Alizadeh, R. A. De Boer, M. Bruinenberg, L. Franke, P. Van Der Harst, H. L. Hillege, M. M. Van Der Klauw, G. Navis, J. Ormel, J. G.M. Rosmalen, J. P. Slaets, H. Snieder, R. P. Stolk, B. H.R. Wolffenbuttel

Research output: Contribution to journalArticlepeer-review

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=5.43×10 -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 (US)
Pages (from-to)60-75
Number of pages16
JournalEuropean Respiratory Journal
Volume45
Issue number1
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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