Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages
- 1School of Clinical and Experimental Medicine, University of Birmingham, UK
- 2Heart of England NHS Trust, Bordesley Green, Birmingham, UK
- 3Lung Investigation Unit, University Hospitals Birmingham, Birmingham, UK
- Correspondence to A M Wood, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK;
Contributors AMW conceived the study, performed AATD genotyping, DBP measurements and statistical analysis, and drafted the paper. CRB and DW performed the efferocytosis assays. PRN performed control and COPD genotyping. DRT and RAS supervised the work and reviewed the manuscript.
- Received 19 April 2010
- Accepted 2 November 2010
- Published Online First 12 January 2011
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 (FEV1) (p=0.02), in direct contrast to vitamin D, where deficiency related to low FEV1 (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 FEV1, and affects macrophage activation. Vitamin D effects may be independent of this, relating more strongly to innate immunity.
See Editorial, p 189
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Funding Talecris Biotherapeutics (non-commercial grant) and the West Midlands Chest Fund funded the majority of this work. DRT is also funded by the Wellcome Trust.
Competing interests None.
Ethics approval This study was conducted with the approval of the South Birmingham LREC refs. 3359, 3359a and 07/H1207/231, and North West REC ref. 07/MRE08/42.
Provenance and peer review Not commissioned; externally peer reviewed.