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Polymorphic Changes in the 5´ Flanking Region of Factor VII Have a Combined Effect on Promoter Strength

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Issue: 2002: 88/5 (Nov) pp.703-887
Pages: 763-767

Polymorphic Changes in the 5´ Flanking Region of Factor VII Have a Combined Effect on Promoter Strength

Rama Kudaravalli (1), Theresa Tidd (1), Mirko Pinotti (2), Antonia Ratti (1, 3), Rosa Santacroce (1, 4), Maurizio Margaglione (4), Bruno Dallapiccola (4, 5), Francesco Bernardi (2), Paolo Fortina (1), Marcella Devoto (6), Eleanor S. Pollak (1)
(1) The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; (2) Dipartimento di Biochimica e Biologia Molecolare, University of Ferrara, Ferr

Summary

Polymorphic differences in the 5’ flanking region of the gene encod-ing procoagulant protein Factor VII (FVII) are associated with varia-tions 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.