Polymorphism in the alpha(1)-antichymotrypsin (ACT) gene promoter: effect on expression in transfected glial and liver cell lines and plasma ACT concentrations

Alpha(1)-antichymotrypsin (ACT: new identification SERPINA3) is a member of the serine proteinase inhibitor (serpin) gene family and biochemically has been shown to be a constituent of the senile plaques of Alzheimer's diseas e. We describe a polymorphism (G-->T) in the promoter region of the ACT gen e with the T allele being associated with a 22% increase in the mean plasma ACT concentrations. By reporter gene studies, the T allele is consistently associated with higher mean basal expression in both the human liver cell- line Hep G2 (32%) and in a human glial cell-line T98G (30%). Following 6-h stimulation with the cytokine oncostatin-M, there was a 30-fold increase in Hep G2 and a four-fold increase in T98G cells. The T allele in the promote r region is also in almost complete linkage disequilibrium with the T allel e in the signal peptide region of the ACT gene with a standardised disequil ibrium coefficient (D') of 0.97; P<0.001. This is the first description of a polymorphism in the ACT gene promoter directly associated with altered ge ne expression.