Biochemical intermediates in α1‐antitrypsin deficiency: Residual family resemblance for total α1‐antitrypsin, oxidized α1‐antitrypsin, and immunoglobulin E after adjustment for the effect of the Pi locus

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Abstract
α1‐antitrypsin (α1AT) deficiency is variably associated with the development of pulmonary emphysema. To gain insight into the process which begins the Z point mutation at the Protease Inhibitor (Pi) locus and results in the variable development of emphysema, three quantitative phenotypes, including total α1AT, oxidized α1AT, and total immunoglobulin E (IgE), were measured in sera from α1‐antitrypsin‐deficient individuals and their families. The mean and variance effects of the Pi locus on these biochemical phenotypes were removed, and path analysis of the residual phenotypes was performed by using a TAU model to investigate whether there was any additional multifactorial transmission. Significant transmission was demonstrated for total serum IgE and serum‐oxidized α1AT, which could be due to major genes other than the Pi locus, polygenes, or familial environment. Segregation analysis of the residual phenotypes was performed to determine whether additional major gene effects, other than the Pi effect, influence these quantitative phenotypes. Convincing evidence for an additional major gene was not found for oxidized α1AT, total α1AT, or IgE.