An alpha(1)-antitrypsin enhancer polymorphism is a genetic modifier of pulmonary outcome in cystic fibrosis

Lung disease is the direct cause of death in over 90% of cystic fibrosis (C F) patients. Excess neutrophil elastase is an important determinant of pulm onary disease in CF, alpha (1)-antitrypsin (AAT), also known as alpha (1)-p roteinase inhibitor (alpha 1PI) is a major modulator of elastase activity. We investigated the hypothesis that an enhancer polymorphism in the AAT gen e would contribute to pulmonary prognosis in CF. Respiratory function, ches t X-ray scores, bacterial colonisation and infective exacerbation were asse ssed to evaluate pulmonary disease severity in the CF group. Sixteen patien ts were found to have the 1237A allele, and 108 the more frequent G allele. Contrary to expectation, the patients with the 1237A allele were found to have better indices of pulmonary disease progression than those without, as indicated by less change in X-ray score (1237A: 0.2+/-0.1; 1237G: 1.2+/-0. 1; P=0.002) and fewer infective exacerbations (1237A: 2.8+/-0.6; 1237G: 4.6 +/-0.3; P=0.03) over the preceding 2 years. Also, a higher proportion of th e 1237A (25%) than the 1237G (6.5%) were not colonised by Pseudomonas Aerug inosa (P=0.04). Prospective monitoring of infections for a further 2 years confirmed a lesser propensity to infection in patients with the 1237A allel e. These trends were also observed in a tightly matched sub-set of CF genot ypes of similar age and sex, thus confirming that these effects were indepe ndent of the CF genotype. These results indicate that this AAT enhancer pol ymorphism is associated with better pulmonary prognosis in CF. Though the n umber of CF patients with the polymorphism is small, and these data need to be confirmed in larger studies, they suggest that a cautious approach shou ld perhaps be taken to treatment of CF patients with supplemental AAT.