title: Family study of alpha 1-antitrypsin deficiency: effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits.
abstract: To gain insight into the variable expression of lung disease in alpha 1-antitrypsin (alpha 1AT) 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 alpha 1AT, oxidized serum alpha 1AT, and total serum immunoglobulin E (IgE) were measured in alpha 1AT 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 alpha 1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV1, FEF25-75, and oxidized alpha 1AT 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 of the Pi x pack-years 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, (FEVf12,) 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.
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis 63110.
authors.forename: E K
authors.initials: EK
authors.lastname: Silverman
authors.forename: M A
authors.initials: MA
authors.lastname: Province
authors.forename: E J
authors.initials: EJ
authors.lastname: Campbell
authors.forename: J A
authors.initials: JA
authors.lastname: Pierce
authors.forename: D C
authors.initials: DC
authors.lastname: Rao
mesh_terms: D005190:Family; D005260:Female; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D008173:Lung Diseases, Obstructive / Q000201:enzymology / Q000235:genetics; D008297:Male; D010641:Phenotype; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000235:genetics; D015656:Respiratory Mechanics; D012307:Risk Factors; D012907:Smoking; D011795:Surveys and Questionnaires; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency
chemical_list: D000515:alpha 1-Antitrypsin; D007073:Immunoglobulin E