Variability of Pulmonary Function in Alpha-1-Antitrypsin Deficiency: Residual Family Resemblance beyond the Effect of the Pi Locus

• Published in: Human heredity 1990, Vol.40 (6), p.340-355
• Main Authors: Silverman, Edwin K., Province, Michael A., Campbell, Edward J., Pierce, John A., Rao, D.C.
• Format: Article
• Language: English
• Subjects: alpha 1-Antitrypsin - genetics; Biological and medical sciences; Factor Analysis, Statistical; Forced Expiratory Volume; Genotype; Humans; Lung - physiopathology; Maximal Midexpiratory Flow Rate; Medical sciences; Models, Genetic; Original Paper; Original Papers; Pneumology; Smoking
• ISSN: 0001-5652; 1423-0062
• DOI: 10.1159/000153958

To gain insight into the variable expression of lung disease in α₁-antitrypsin deficiency, two pulmonary function tests, FEV₁ and FEF25-75, were examined in α₁-antitrypsin-deficient individuals and their families. The mean and variance effects of Pi type, age, and sex on the pulmonary function variables were removed by stepwise multiple regression, and the residual phenotypes were analyzed. Path analysis of the residual phenotypes with environmental indices in 46 nuclear families demonstrated higly significant cultural inheritance. Significant polygenic inheritance was not demonstrated for FEV₁ but was shown for FEF25-75. For FEV₁, adjustment for the significant interaction between Pi type and pack-years of smoking tended to increase the estimated contribution of polygenic inheritance and to decrease the estimated contribution of cultural inheritance. Segregation analysis of the residual phenotypes in 44 nuclear families was carried out to determine whether another major gene, other than the Pi locus, may be influencing pulmonary function in this population. Statistical evidence was found for an additional major gene influencing FEV₁; however, the evidence diminished after adjusting for the effects of pack-years and the interaction between Pi type and pack-years. This apparent drop in the importance of genetic factors would not be surprising if the effect of the putative major gene is to enhance susceptibility to effects of cigarette smoking. Finally, our investigation demonstrates the feasibility of dissecting residual familial effects on complex multifactorial traits.