Alpha1-antitrypsin deficiency alleles and the Taq-I G-->A allele in cystic fibrosis lung disease

• Published in: The European respiratory journal Vol. 11; no. 4; pp. 873 - 879
• Main Authors: Mahadeva, R, Westerbeek, RC, Perry, DJ, Lovegrove, JU, Whitehouse, DB, Carroll, NR, Ross-Russell, RI, Webb, AK, Bilton, D, Lomas, DA
• Format: Journal Article
• Language: English
• Published: England Eur Respiratory Soc 01-04-1998
• Subjects: Adult; Alleles; alpha 1-Antichymotrypsin - genetics; alpha 1-Antitrypsin Deficiency - genetics; C-Reactive Protein - genetics; Cystic Fibrosis - genetics; Cystic Fibrosis - physiopathology; Female; Humans; Lung - physiopathology; Male; Phenotype
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/09031936.98.11040873

Cystic fibrosis (CF) is characterized by progressive and ultimately fatal pulmonary disease although there are notable variations in clinical features. This heterogeneity is thought to lie outside the cystic fibrosis transmembrane regulator (CFTR) gene locus and may stem from deficiencies in the antiproteinase screen that protects the lung from proteolytic attack. One hundred and fifty seven patients were recruited from two UK CF centres. The serum concentrations of alpha1-antitrypsin, alpha1-antichymotrypsin and C-reactive protein (CRP) were determined and patients were screened for the common S and Z deficiency alleles of alpha1-antitrypsin and the G-->A mutation in the 3' noncoding region of the alpha1-antitrypsin gene (Taq-I G-->A allele). Alpha1-antitrypsin deficiency phenotypes were detected in 20 (16 MS, 1 S and 3 MZ) out of 147 unrelated tested CF patients and were, surprisingly, associated with significantly better lung function (adjusted mean forced expiratory volume in one second (FEV1) 62.5% of predicted for deficient group and 51.1% pred for normal alleles; p=0.043). The Taq-I G-->A allele was found in 21 out of 150 unrelated patients and had no significant effect on CF lung disease or on levels of alpha1-antitrypsin during the inflammatory response. We show here that, contrary to current thinking, common mutations of alpha1-antitrypsin that are associated with mild to moderate deficiency of the protein predict a subgroup of cystic fibrosis patients with less severe pulmonary disease. Moreover, the Taq-I G-->A allele has no effect on serum levels of alpha1-antitrypsin in the inflammatory response, which suggests that the previously reported association of the Taq-I G-->A allele with chronic obstructive pulmonary disease is not mediated by its effect on the serum level of alpha1-antitrypsin.