Does the PI polymorphism alone control alpha-1-antitrypsin expression

Whether genetic factors other than the protease-inhibitor (PI) poly-morphism itself contribute to variation in alpha-I-antitrypsin is of both theoretical and practical interest. We have measured the quantity of alpha-I-antitrypsin (by an immunoturbidometric assay) and its activ-ity (by assaying elastase, inhibitory capacity [EICD in 583 individuals from 114 twin kinships who were also typed for PI by isoelectric focusing. Models of variation were fitted directly to the raw observa-tions by a maximum-likelihood method. Specification of phenotypic means led to highly significant improvements in fit over models includ-ing only individual environment variance and additive genetic vari-ance. The 29 phenotype means could also be described as the appro-priate additive combinations of the 12 allelic effects. Only small improvements in fit could then be obtained by addition of polygenic components of variance. We conclude that nearly all genetic variation in alpha-I-antitrypsin quantity and activity can be explained by de-tectable variation at the PI locus and that this variance is largely additive. Bivariate analysis of alpha-I-antitrypsin and EIC revealed marginal evidence for differences. in specific activities of molecules coded by different PI alleles. The correlation between environmental deviations for the two measures was only.63, which may reflect, in part, the rather low reliability of the assays and account for the mod-est heritabilities «.5) of the two measures. An intriguing finding was the presence of significant differences in El variance for different PI types, suggesting that different phenotypes have differing capacities to react to environmental challenges