title: SERPINA1 11478G→A variant, serum α1-antitrypsin, exacerbation frequency and FEV1 decline in COPD.
abstract: BACKGROUND
  The α(1)-antitrypsin 11478G→A polymorphism may be associated with attenuated acute α(1)-antitrypsin responses. It was hypothesised that patients with chronic obstructive pulmonary disease (COPD) and this mutation have accelerated lung function decline.
  
  
  OBJECTIVE
  To assess whether the 11478G→A polymorphism is associated with attenuated α(1)-antitrypsin responses at COPD exacerbation, and therefore accelerated lung function decline.
  
  
  METHODS
  Lung function decline by genotype was examined in the English Longitudinal Study of Ageing (ELSA; n=1805) and Whitehall II (n=2733) studies. 204 patients with COPD were genotyped in the London cohort and serum α(1)-antitrypsin concentration was measured at baseline and (n=92) exacerbation.
  
  
  RESULTS
  The 11478G→A genotype frequencies did not vary between COPD cases and controls, or between COPD frequent and infrequent exacerbators. Subjects with the rare A allele experienced more rapid lung function decline in the Whitehall II (A vs non-A: 16 vs 4 ml/year p=0.02) but not ELSA (29 vs 34 ml/year, p=0.46) or London cohorts (26 vs 38 ml/year, p=0.06). Decline was not greater in frequent exacerbator A versus non-A carriers (20 vs 24 ml/year, p=0.58). Upregulation of α(1)-antitrypsin at exacerbation was not demonstrated, even in patients homozygous for the common allele (median exacerbation change -0.07 g/l 11478GG, p=0.87 and -0.09 g/l 11478AA/GA, p=0.92; p=0.90 for difference). In patients with the A allele, there was no correlation between serum α(1)-antitrypsin and serum interleukin 6 (IL-6) concentrations.
  
  
  CONCLUSIONS
  The 11478G→A α(1)-antitrypsin polymorphism is not associated with increased risk of developing COPD, nor accelerated lung function decline. Serum α(1)-antitrypsin may not be upregulated early at COPD exacerbation. In patients with the 11478G→A polymorphism there was no relationship between the serum α(1)-antitrypsin and serum IL-6 concentrations.
authors.affiliation: Academic Unit of Respiratory Medicine, University College London, London, UK.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Quint
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Donaldson
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: John R
authors.initials: JR
authors.lastname: Hurst
mesh_terms: D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D000515:alpha 1-Antitrypsin / Q000097:blood* / Q000235:genetics
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D002097:C-Reactive Protein