Polymorphic changes in the 5' flanking region of factor VII have a combined effect on promoter strength.
Polymorphic differences in the 5' flanking region of the gene encoding procoagulant protein Factor VII (FVII) are associated with variations in FVII coagulant activity (FVII:C) and FVII antigen (FVII:Ag) levels. A decanucleotide insert polymorphism (CCTATATCCT) at 323 bp upstream of the start site of translation correlates with a decrease of approximately 20% FVII: C levels per allele containing this insert. However, linkage disequilibrium of the decanucleotide polymorphism with two single nucleotide polymorphisms (SNPs) at -122 and -401 have made it difficult to pinpoint the functional role, if any, of these genetic changes in lowering FVII levels. In vitro reporter gene studies in HepG2 cells analyzing the 8 possible combinations of polymorphic sites at -401, -323, and -122 reveal the necessity of the presence of the three concurrent polymorphic changes to maximally decrease promoter strength. In addition, these in vitro results are supported by in vivo studies in 89 individuals of African heritage, 34% of whom display a new haplotype that shows the polymorphic changes at -323 and -401 but lacks the change at -122.
Kudaravalli
Rama
R
The Children's Hospital of Philadelphia, PA, USA.
Tidd
Theresa
T
Pinotti
Mirko
M
Ratti
Antonia
A
Santacroce
Rosa
R
Margaglione
Maurizio
M
Dallapiccola
Bruno
B
Bernardi
Francesco
F
Fortina
Paolo
P
Devoto
Marcella
M
Pollak
Eleanor S
ES
D024506:5' Flanking Region / Q000235:genetics*; D000349:Africa / Q000208:ethnology; D000595:Amino Acid Sequence; D044383:Black People / Q000235:genetics; D005167:Factor VII / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D005167:Factor VII