Association of alpha(1)-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis.
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 alpha(1)-antitrypsin have less, rather than more, severe pulmonary disease. Alpha(1)-antichymotrypsin is another important serine proteinase inhibitor that protects the lung against proteolytic attack, and point mutations in the alpha(1)-antichymotrypsin gene that result in plasma deficiency are associated with chronic obstructive pulmonary disease.


METHODS
The effect of alpha(1)-antichymotrypsin deficiency and the -15 alpha(1)-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 alpha(1)-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 alpha(1)-antichymotrypsin: forced expiratory volume in one second (FEV(1)) 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 alpha(1)-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.


CONCLUSIONS
These data indicate that deficiency of alpha(1)-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.
Mahadeva
R
R
Respiratory 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. rm232@cam.ac.uk
Sharples
L
L
Ross-Russell
R I
RI
Webb
A K
AK
Bilton
D
D
Lomas
D A
DA
D000328:Adult; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000503:physiopathology; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D005838:Genotype; D006801:Humans; D008171:Lung Diseases / Q000150:complications* / Q000503:physiopathology; D008297:Male; D015999:Multivariate Analysis; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology; D000514:alpha 1-Antichymotrypsin / Q000097:blood / Q000172:deficiency* / Q000235:genetics
D021382:Protein Sorting Signals; D000514:alpha 1-Antichymotrypsin