FAMILY STUDY OF ALPHA-1-ANTITRYPSIN DEFICIENCY - EFFECTS OF CIGARETTE-SMOKING, MEASURED GENOTYPE, AND THEIR INTERACTION ON PULMONARY-FUNCTION AND BIOCHEMICAL TRAITS

To gain insight into the variable expression of lung disease in alpha1-antitrypsin (alpha1AT) deficiency, five quantitative variables including forced expiratory volume at 1 sec (FEV1), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF25-75), total serum alpha1AT, oxidized serum alpha1AT, and total serum immunoglobulin E (IgE) were measured in alpha1AT deficient individuals and their families. The effect of a known, measured genotype (the Pi type) was estimated for each quantitative trait; the influence of mode of case ascertainment on the measured genotype effect was also assessed. These analyses showed that total alpha1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV1, FEF25-75, and oxidized alpha1AT are moderately influenced by Pi type. The effect of genotype-by-environment interaction between Pi type and pack-years of cigarette smoking on the five quantitative phenotypes was studied using an analysis of covariance. Significant Pi x pack-years interaction was evident for FEV1, but this effect is confounded in this data set with the Pi x age interaction. Probands who were ascertained because they had chronic obstructive pulmonary disease (COPD) do not demonstrate the significant Pi x pack-years interaction effect on FEV1 which Pi Z subjects ascertained for other reasons demonstrate. The effect of the Pi x pack-years interaction on FEV1 was no longer significant on a transformed scale, (FEV1(2),) thus providing an additive scale for future data analysis. The increased sensitivity of Pi MZ individuals in our sample to cigarette smoking reduced the Pi x packs-years interaction effect on FEF25-75 to borderline significance. This investigation has provided an opportunity to incorporate both measured genotype and genotype-by-environment interaction analyses into the study of the variable expression of lung disease in Pi Z individuals.