title: Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.
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.
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section d.s.postma@umcg.nl.
authors.forename: Akkelies E
authors.initials: AE
authors.lastname: Dijkstra
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Vonk
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Burkart
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Ani
authors.initials: A
authors.lastname: Manichaikul
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Tess D
authors.initials: TD
authors.lastname: Pottinger
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: David C
authors.initials: DC
authors.lastname: Nickle
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: de Koning
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Lammers
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Pieter
authors.initials: P
authors.lastname: Zanen
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Joanna
authors.initials: J
authors.lastname: Smolonska
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Ciska
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.affiliation: For lists of the authors' affiliations, and the LifeLines Cohort Study group members and their affiliations, see the Acknowledgements section.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
mesh_terms: D000483:Alleles; D001706:Biopsy; D001980:Bronchi / Q000473:pathology; D015331:Cohort Studies; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D006801:Humans; D008168:Lung / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism*; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
chemical_list: C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger