title: Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages.
abstract: BACKGROUND
  Vitamin D-binding protein (DBP) genetic polymorphisms have been associated with chronic obstructive pulmonary disease (COPD). DBP has an indirect role in macrophage activation; thus it was hypothesised that DBP is present in the airway and contributes to lung disease by this mechanism.
  
  
  METHODS
  471 PiZZ subjects with α1-antitrypsin deficiency (AATD) were genotyped for tag single nucleotide polymorphisms (SNPs) covering the DBP gene (GC), together with known functional variants, prior to seeking association with COPD phenotypes. 140 subjects with usual COPD and 480 controls were available for replication. Vitamin D and DBP levels were measured by tandem mass spectrometry and ELISA, respectively, in serum and DBP in the sol phase of sputum in a subset of 60 patients. Concentrations were related to phenotype and to alveolar macrophage activation.
  
  
  RESULTS
  rs2070741 was associated with airway bacterial colonisation (p=0.04) and bronchiectasis (p=0.01), as was rs7041 (p=0.03) which also influenced vitamin D concentrations (p=0.01). The GC2 variant predisposed to bronchiectasis in AATD (p=0.04) and protected against COPD (p=0.05); the latter association was replicated in usual COPD versus controls (p=0.04). Circulating DBP related inversely to forced expiratory volume in 1 s (FEV(1)) (p=0.02), in direct contrast to vitamin D, where deficiency related to low FEV(1) (p=0.04). Sol DBP related directly to alveolar macrophage activation (p=0.004).
  
  
  CONCLUSIONS
  The genetic association of DBP with COPD may be mediated by effects on macrophage activation, since DBP relates to FEV(1), and affects macrophage activation. Vitamin D effects may be independent of this, relating more strongly to innate immunity.
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK. a.m.wood@bham.ac.uk
authors.forename: A M
authors.initials: AM
authors.lastname: Wood
authors.forename: C
authors.initials: C
authors.lastname: Bassford
authors.forename: D
authors.initials: D
authors.lastname: Webster
authors.forename: P
authors.initials: P
authors.lastname: Newby
authors.forename: P
authors.initials: P
authors.lastname: Rajesh
authors.forename: R A
authors.initials: RA
authors.lastname: Stockley
authors.forename: D R
authors.initials: DR
authors.lastname: Thickett
mesh_terms: D000328:Adult; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008262:Macrophage Activation / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D014797:Vital Capacity / Q000502:physiology; D014808:Vitamin D Deficiency / Q000150:complications; D014809:Vitamin D-Binding Protein / Q000097:blood / Q000235:genetics / Q000502:physiology*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000235:genetics
chemical_list: D014809:Vitamin D-Binding Protein