title: Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses.
abstract: BACKGROUND
  Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways.
  
  
  OBJECTIVE
  To investigate the genetic component of AWT.
  
  
  METHODS
  AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated.
  
  
  RESULTS
  Three significant loci on chromosomes 2q (rs734556; P =  6.2 × 10(-7)) and 10q (rs10794108, P = 8.6 × 10(-8); rs7078439, P = 2.3 × 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10(-8), 7.4 × 10(-8), and 7.5 × 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10(-7)) and rs4796712 in NT5C3B (P = 3.1 × 10(-6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10(-41)).
  
  
  CONCLUSIONS
  Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.
authors.affiliation: 1 Department of Pulmonary Diseases.
authors.forename: Akkelies E
authors.initials: AE
authors.lastname: Dijkstra
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Bram
authors.initials: B
authors.lastname: van Ginneken
authors.forename: Mark O
authors.initials: MO
authors.lastname: Wielpütz
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Becker
authors.forename: Michael
authors.initials: M
authors.lastname: Owsijewitsch
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Kauczor
authors.forename: Harry J
authors.initials: HJ
authors.lastname: de Koning
authors.forename: Jan W
authors.initials: JW
authors.lastname: Lammers
authors.forename: Matthijs
authors.initials: M
authors.lastname: Oudkerk
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.forename: David C
authors.initials: DC
authors.lastname: Nickle
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Ciska
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Joanna
authors.initials: J
authors.lastname: Smolonska
authors.forename: Pieter
authors.initials: P
authors.lastname: Zanen
authors.forename: Judith M
authors.initials: JM
authors.lastname: Vonk
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D056151:Airway Remodeling / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000235:genetics; D051528:Guanylate Kinases; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D011656:Pulmonary Emphysema / Q000235:genetics; D058258:Serpin E2 / Q000235:genetics; D014057:Tomography, X-Ray Computed
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D006023:Glycoproteins; C545486:SERPINE2 protein, human; D058258:Serpin E2; D051528:Guanylate Kinases; C485777:MAGI2 protein, human; D015720:5'-Nucleotidase; C412794:NT5C3A protein, human
keywords: COPD; CT scan; airway wall thickening; genetics; smoking