ALPHA-ANTITRYPSIN DEFICIENCY ALLELES AND THE TAQ-I G-]A ALLELE IN CYSTIC-FIBROSIS LUNG-DISEASE

Cystic fibrosis (CF) is characterized by progressive and ultimately fa tal pulmonary disease although there are notable variations in clinica l features. This heterogeneity is thought to lie outside the cystic fi brosis transmembrane regulator (CFTR) gene locus and may stem from def iciencies in the antiproteinase screen that protects the lung from pro teolytic attack. One hundred and fifty seven patients were recruited f rom two UK CF centres, The serum concentrations of alpha(1)-antitrypsi n, alpha(1)-antichymotrypsin and C-reactive protein (CRP) mere determi ned and patients were screened for the common S and Z deficiency allel es of alpha(1)-antitrypsin and the G-->A mutation in the 3' noncoding region of the alpha(1)-antitrypsin gene (Taq-I G-->A allele), alpha(1) -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 for ced expiratory volume in one second (FEV1) 62.5% of predicted for defi cient 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 sig nificant effect on CF lung disease or on levels of alpha(1)-antitrypsi n during the inflammatory response. We show here that, contrary to cur rent thinking, common mutations of alpha(1)-antitrypsin that are assoc iated with mild to moderate deficiency of the protein predict a subgro up of cystic fibrosis patients with less severe pulmonary disease. Mor eover, the Taq-I G-->A allele has no effect on serum levels of alpha(1 )-antitrypsin in the inflammatory response, which suggests that the pr eviously reported association of the Taq-I G-->A allele with chronic o bstructive pulmonary disease is not mediated by its effect on the seru m level of alpha(1)-antitrypsin.