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

Rama Kudaravalli; Theresa Tidd; Mirko Pinotti; Antonia Ratti; Rosa Santacroce; Maurizio Margaglione; Bruno Dallapiccola; Francesco Bernardi; Paolo Fortina; Marcella Devoto; Eleanor S. Pollak

doi:10.1055/s-0037-1613299

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 88(05): 763-767
DOI: 10.1055/s-0037-1613299

Review Article

Schattauer GmbH

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

Rama Kudaravalli

¹The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

,

Theresa Tidd

¹The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

,

Mirko Pinotti

²Dipartimento di Biochimica e Biologia Molecolare, University of Ferrara, Ferrara, Italy

,

Antonia Ratti

¹The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

³Ospedale Maggiore Policlinico, Dipartimento di Science Neurologiche, University of Milan, Italy

,

Rosa Santacroce

¹The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

⁴Unita’ di Ricerca in Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

,

Maurizio Margaglione

⁴Unita’ di Ricerca in Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

,

Bruno Dallapiccola

⁴Unita’ di Ricerca in Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

⁵Instituto C. S. S. Mendel, Dipartimento di Medicina Sperimentale e Patologia, University La Sapienza – Roma, Italy

,

Francesco Bernardi

²Dipartimento di Biochimica e Biologia Molecolare, University of Ferrara, Ferrara, Italy

,

Paolo Fortina

¹The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

,

Marcella Devoto

⁶Department of Research, Nemours Children’s Clinic, Wilmington, DE and Department of Oncology, Biology, and Genetics, University of Genoa, Genoa, Italy

,

Eleanor S. Pollak

¹The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

› Author Affiliations

Abstract

Summary

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.

Keywords

Factor VII - transcription - polymorphism - decanucleotide - African American

Full Text

References

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