α1-Antitrypsin deficiency alleles and the Taq-I G→A allele in cystic fibrosis lung disease

Cystic fibrosis (CF) is the commonest autosomal recessive genetic disorder amongst populations of northern European descent. Most patients succumb to progressive pulmonary disease, although there are considerable variations in clinical features [1, 2]. The pulmonary heterogeneity is largely independent of mutations within the cystic fibrosis transmembrane regulator (CFTR) gene on chromosome 7 [2] although recent reports have suggested that milder lung disease may occur in CF patients who are compound heterozygotes for less common mutations [3, 4]. The variability of pulmonary disease in patients with the same genotype has been ascribed to the pancreatic status of individuals, treatment regimes, social class, smoking history and colonization with Pseudomonas aeruginosa or Burkholderia cepacia [5–10]. Studies of twins suggest that genetic factors lying outside the CFTR locus may be linked to pulmonary phenotype [11] and although one such factor has been suggested [12], none have been confirmed to date. A major cause of the chronic pulmonary disease in CF is a persistent imbalance between neutrophil proteinases, most importantly elastase, and the host defence screen, spearheaded by α1-antitrypsin (α1-AT) [13, 14]. α1-AT is a 52 kDa acute-phase glycoprotein secreted by the liver and monocytes and is the most important proteinase inhi-bitor in the lung. Over 70 variants have been described by isoelectric focusing, but the most clinically important are the common S (264glutamic acid (Glu)→valine (Val)) and Z (342Glu→lysine (Lys)) alleles which are found in ap-proximately 12% of the UK population [15] and result in plasma α1-AT levels in the homozygote of 60% and 10%, respectively, when compared to the normal M homozygote. "Relative" α1-AT deficiency may be associated with the Taq-I G→A allele at the polymorphic site in the 3' noncoding region enhancer binding element of the α1antitrypsin gene [16]. This mutant allele results in the loss of a Taq-I restriction site and may reduce the rise in the level of α1-antitrypsin in the acute phase response, whilst leaving baseline levels unaffected. The presence of the G→A allele has been found to confer a 13 fold increased risk for the development of chronic airflow obstruction [17, 18]. α1-Antitrypsin deficiency alleles and the Taq-I G→A allele in cystic fibrosis lung disease. R. Mahadeva, R.C. Westerbeek, D.J. Perry, J.U. Lovegrove, D.B. Whitehouse, N.R. Carroll, R.I. Ross-Russell, A.K. Webb, D. Bilton, D.A. Lomas. ©ERS Journals Ltd 1998. ABSTRACT: 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 α1-antitrypsin, α1-antichymotrypsin and C-reactive protein (CRP) were determined and patients were screened for the common S and Z deficiency alleles of α1-antitrypsin and the G→A mutation in the 3' noncoding region of the α1-antitrypsin gene (Taq-I G→A allele). α1-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 α1-antitrypsin during the inflammatory response. We show here that, contrary to current thinking, common mutations of α1-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 α1-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 α1-antitrypsin. Eur Respir J 1998; 11: 873–879. *Depts of Medicine and Haematology, University of Cambridge, UK. **Cystic Fibrosis Unit, Papworth Hospital, Cambridge, UK. +Medical Research Council Biostatistics Unit, University of Cambridge, UK. ++The Royal Free Hospital School of Medicine, London, UK. #Medical Research Council Human Biochemical Genetics Unit, University College London, UK. Depts of ##Radiology and †Paediatrics, Addenbrooke's Hospital, Cambridge, UK. ‡The Bradbury Cystic Fibrosis Unit, Wythenshawe Hospital, Manchester, UK.