Family study of α₁‐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 α₁‐antitrypsin (α1AT) deficiency, five quantitative variables including forced expiratory volume at 1 sec (FEV₁), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF_25–75), total serum α1AT, oxidized serum α1AT, and total serum immunoglobulin E (IgE) were measured in α1AT 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 α1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV₁, FEF_25–75, and oxidized α1AT 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 × pack‐years interaction was evident for FEV₁, but this effect is confounded in this data set with the Pi × age interaction. Probands who were ascertained because they had chronic obstructive pulmonary disease (COPD) do not demonstrate the significant Pi × pack‐years interaction effect on FEV₁ which Pi Z subjects ascertained for other reasons demonstrate. The effect of the Pi × pack‐years interaction on FEV₁ was no longer significant on a transformed scale, (FEV₁²,) 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 × packs‐years interaction effect on FEF_25–75 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. © 1992 Wiley‐Liss, Inc.