SERPINA1 11478G→A variant, serum α1-antitrypsin, exacerbation frequency and FEV1 decline in COPD
- 1Academic Unit of Respiratory Medicine, University College London, London, UK
- 2Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK
- 3Centre for Cardiovascular Genetics, Institute of Cardiovascular Research, University College London, London, UK
- Correspondence to John R Hurst, Academic Unit of Respiratory Medicine, Royal Free Campus, UCL Medical School, Rowland Hill Street, London NW3 2PF, UK;
Contributors All authors contributed to the design and interpretation of data, and have approved the final version of the manuscript. JRH devised the hypothesis for the study. JKQ coordinated the London cohort studies and led the analysis of this data with GCD. The genotyping was performed in the laboratories of PJT. MK led the analysis of the Whitehall and ELSA data.
- Received 6 October 2010
- Accepted 20 January 2011
- Published Online First 18 February 2011
Background The α1-antitrypsin 11478G→A polymorphism may be associated with attenuated acute α1-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 α1-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 α1-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 α1-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 α1-antitrypsin and serum interleukin 6 (IL-6) concentrations.
Conclusion The 11478G→A α1-antitrypsin polymorphism is not associated with increased risk of developing COPD, nor accelerated lung function decline. Serum α1-antitrypsin may not be upregulated early at COPD exacerbation. In patients with the 11478G→A polymorphism there was no relationship between the serum α1-antitrypsin and serum IL-6 concentrations.
- lung function
- alpha1 antitrypsin deficiency
- COPD mechanisms
- COPD exacerbations
- COPD pathology
Funding The Whitehall II study has been supported by grants from the Medical Research Council (MRC); Economic and Social Research Council; British Heart Foundation (RG/02/005; PG/03/029); Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (HL36310); US NIH National Institute on Aging (AG13196); US NIH Agency for Health Care Policy Research (HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. The US National Institute on Aging (grant numbers R01AG24233, R01AG1764406S1) funds the English Longitudinal Study of Ageing DNA Repository (EDNAR) and ELSA is funded by the National Institute of Aging in the USA, and a consortium of UK Government departments coordinated by the Office for National Statistics. PJT is funded by the British Heart Foundation (RG/05/014). The London COPD cohort is funded by the UK MRC.
Competing interests None.
Ethics approval The London COPD cohort work was conducted with approval of the Royal Free Hospital Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.