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

Background-Alpha-1 antitrypsin (alpha(1)-AT) is the most abundant proteinas e inhibitor within the lung. We have recently reported the surprising obser vation that cystic fibrosis patients with mild to moderate deficiency of al pha(1)-antitrypsin have significantly better pulmonary function than non-de ficient 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 hav e undergone orthotopic lung transplantation. The prevalence of alpha(1)-ant itrypsin deficiency alleles in this most severely affected group of patient s with cystic fibrosis was therefore assessed. Methods-DNA was obtained from neonatal blood spots from children with cysti c fibrosis who had died from pulmonary disease and from formalin fixed lung tissue from transplanted cystic fibrosis patients. The common S and Z defi ciency alleles of alpha(1)-AT were sought by amplification mutagenesis of t he appropriate region of the alpha(1)-AT gene followed by restriction enzym e 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 fibrosi s and may be associated with milder lung disease. Further work is needed to clarify the mechanisms underlying the progressive lung damage in cystic fi brosis.