Alpha-1 antitrypsin deficiency alleles and severe cystic fibrosis lung disease

Background-Alpha-1 antitrypsin (alpha(1)-AT) is the most abundant proteinase inhibitor within the lung. We have recently reported the surprising observation that cystic fibrosis patients with mild to moderate deficiency of alpha(1)-antitrypsin have significantly better pulmonary function than non-deficient patients. This study may have been biased as it did not include the most severely affected patients who have died in childhood or hose who have undergone orthotopic lung transplantation. The prevalence of alpha(1)-antitrypsin deficiency alleles in this most severely affected group of patients with cystic fibrosis was therefore assessed. Methods-DNA was obtained from neonatal blood spots from children with cystic fibrosis who had died from pulmonary disease and from formalin fixed lung tissue from transplanted cystic fibrosis patients. The common S and Z deficiency alleles of alpha(1)-AT were sought by amplification mutagenesis of the appropriate region of the alpha(1)-AT gene followed by restriction enzyme digestion with Xmn I and Tag I, respectively. Results-Seventy nine patients were identified (seven dead, 72 transplanted). Two patients (2.5%) were heterozygous for the Z allele of alpha(1)-AT and four (5.1%) were heterozygous for the S allele. This is not significantly different from the incidence in the normal population of 4% and 8% for the S and Z alleles, respectively. Conclusions-These data support previous findings that deficiency of alpha(1)-AT is not associated with more severe pulmonary disease in cystic fibrosis and may be associated with milder lung disease. Further work is needed to clarify the mechanisms underlying the progressive lung damage in cystic fibrosis.