Polymorphism in the alpha(1)-antichymotrypsin (ACT) gene promoter: effect on expression in transfected glial and liver cell lines and plasma ACT concentrations.
Alpha1-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 disease. We describe a polymorphism (G-->T) in the promoter region of the ACT gene 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 promoter region is also in almost complete linkage disequilibrium with the T allele in the signal peptide region of the ACT gene with a standardised disequilibrium 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 gene expression.
Morgan
K
K
Division of Clinical Chemistry, School of Clinical Laboratory Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK.
Licastro
F
F
Tilley
L
L
Ritchie
A
A
Morgan
L
L
Pedrini
S
S
Kalsheker
N
N
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009457:Neuroglia / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014162:Transfection; D000514:alpha 1-Antichymotrypsin / Q000097:blood* / Q000235:genetics*
D000514:alpha 1-Antichymotrypsin; D004247:DNA