α1-antitrypsin deficiency alleles in cystic fibrosis lung disease

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genotype does not explain the heterogeneity observed in CF pulmonary disease severity. Modifier genes are implicated for this heterogeneity. alpha(1)-antitrypsin (alpha(1)-AT) is one of the few antiproteases capable of inactivating neutrophil elastase. We investigated whether alpha(1)-AT alleles (Z, S deficiency alleles and the 3 'G(1237)-->A mutation) were associated with increased disease severity and the alpha(1)-AT acute phase response during pulmonary exacerbations. This was a multicenter Canadian study. Seven hundred sixteen patients with CF (age range, 5.0-63.6 yr) were genotyped for the Z, S, and G(1237)-->A polymorphisms of the alpha(1)-AT gene. Stable and acute levels of alpha(1)-AT were ' measured on 31 adult patients with CF and were correlated,to clinical parameters. There were 69, 13, and 18 patients with CF who were MS, SS, and MZ, respectively. There were 95 and 7 patients with CF heterozygous or homozygous for the A(1237) allele, respectively. alpha(1)-AT genotype did not predict pulmonary disease severity, and was not associated with more severe clinical outcome (death or lung transplantation) or age of onset of Pseudomonas aeruginosa infection. Body mass index was a significant predictor lof alpha(1)-AT levels during exacerbations. alpha(1)-AT genotype is not a major contributor to the variability of pulmonary disease severity in CF.