A Family Study of the Variability of Pulmonary Function in α1-Antitrypsin Deficiency: Quantitative Phenotypes

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Abstract
A group of 52 .alpha.1-antitrypsin-deficient individuals of phenotype Pi Z and 117 of their relatives underwent a protocol including pulmonary function testing, completion of a questionnaire, and blood donation. Our population permitted a minimum frequency estimate (7 .times. 10-4) for Pi null alleles. Five quantitative phenotype were measured, including FEV1, FEF25-75, total serum .alpha.1AT, oxidized serum .alpha.1AT, and total serum IgE. We found that (1) total .alpha.1AT levels were higher in Pi Z subjects with lung function impairment (FEV1 .ltoreq. 65% of predicted) than in Pi Z subjects who were not impaired; (2) Pi Z subjects with lung function impairment had elevated serum levels of oxidized .alpha.1AT; and (3) IgE levels were relatively elevated in first-degree Pi MZ relatives of impaired Pi Z subjects. Moreover, FEV1 tended to be relatively reduced in heterozygous parents of impaired Pi Z subjects, suggesting that a subset of Pi MZ individuals are at risk for development of lung disease because of familial factors. These results represent an initial step toward the development of intermediate phenotypes that will be predictive of a severe course in .alpha.1AT deficiency; they suggest that, in addition to cigarette smoking, atopic predisposition and undetermined familial factors may be important codeterminants of lung disease progression.