title: Polymorphic changes in the 5' flanking region of factor VII have a combined effect on promoter strength.
abstract: 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.
authors.affiliation: The Children's Hospital of Philadelphia, PA, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Kudaravalli
authors.forename: Theresa
authors.initials: T
authors.lastname: Tidd
authors.forename: Mirko
authors.initials: M
authors.lastname: Pinotti
authors.forename: Antonia
authors.initials: A
authors.lastname: Ratti
authors.forename: Rosa
authors.initials: R
authors.lastname: Santacroce
authors.forename: Maurizio
authors.initials: M
authors.lastname: Margaglione
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Francesco
authors.initials: F
authors.lastname: Bernardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Eleanor S
authors.initials: ES
authors.lastname: Pollak
mesh_terms: 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
chemical_list: D005167:Factor VII