Association of α1-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis
- aRespiratory Medicine Unit, Department of Medicine and Department of Haematology, University of Cambridge, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK, bMRC Biostatistics Unit, Forvie Site, Cambridge, UK, cDepartment of Paediatrics, Addenbrooke's Hospital, Cambridge, UK, dThe Bradbury Cystic Fibrosis Unit, Wythenshawe Hospital, Manchester, UK, eCystic Fibrosis Unit, Papworth Hospital, Papworth Everard, Cambridge, UK
- Dr R Mahadevarm232{at}cam.ac.uk
- Received 17 April 2000
- Revision requested 16 June 2000
- Revised 28 July 2000
- Accepted 8 September 2000
Abstract
BACKGROUND Cystic fibrosis (CF) is characterised by an excess of free proteinases that destroy lung tissue. Despite this, previous studies have shown that patients with CF with a mild deficiency variant of the proteinase inhibitor α1-antitrypsin have less, rather than more, severe pulmonary disease. Alpha1-antichymotrypsin is another important serine proteinase inhibitor that protects the lung against proteolytic attack, and point mutations in the α1-antichymotrypsin gene that result in plasma deficiency are associated with chronic obstructive pulmonary disease.
METHODS The effect of α1-antichymotrypsin deficiency and the –15 α1-antichymotrypsin signal peptide genotype on lung function was assessed in patients with CF.
RESULTS One hundred and fifty seven patients with CF were screened and 10 were identified with a plasma deficiency of α1-antichymotrypsin (plasma concentration <0.2 g/l). In a multivariate analysis these individuals had significantly less severe lung disease than those who had normal or raised levels of α1-antichymotrypsin: forced expiratory volume in one second (FEV1) 69.9% predicted versus 53.2% predicted (p=0.04) and chest radiographic score of 7.2 versus 9.7 (p=0.03) for those with and without α1-antichymotrypsin deficiency, respectively. The –15 signal peptide genotype did not affect plasma levels, but the –15 Ala/Ala signal peptide genotype was over-represented in individuals with CF compared with healthy blood donor controls.
CONCLUSION These data indicate that deficiency of α1-antichymotrypsin is associated with less severe pulmonary disease in patients with CF, and support our previous observations that mild genetic deficiency of a proteinase inhibitor is associated with an improved outcome.
