Download PDF
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
1   The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
,
Theresa Tidd
1   The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
,
Mirko Pinotti
2   Dipartimento di Biochimica e Biologia Molecolare, University of Ferrara, Ferrara, Italy
,
Antonia Ratti
1   The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
3   Ospedale Maggiore Policlinico, Dipartimento di Science Neurologiche, University of Milan, Italy
,
Rosa Santacroce
1   The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
4   Unita’ di Ricerca in Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
,
Maurizio Margaglione
4   Unita’ di Ricerca in Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
,
Bruno Dallapiccola
4   Unita’ di Ricerca in Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
5   Instituto C. S. S. Mendel, Dipartimento di Medicina Sperimentale e Patologia, University La Sapienza – Roma, Italy
,
Francesco Bernardi
2   Dipartimento di Biochimica e Biologia Molecolare, University of Ferrara, Ferrara, Italy
,
Paolo Fortina
1   The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
,
Marcella Devoto
6   Department of Research, Nemours Children’s Clinic, Wilmington, DE and Department of Oncology, Biology, and Genetics, University of Genoa, Genoa, Italy
,
Eleanor S. Pollak
1   The Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
› Author Affiliations
Further Information

Publication History

Received 04 April 2002

Accepted after revision 20 June 2002

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

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
 

  • References

  • 1 Fair DS. Quantitation of factor VII in the plasma of normal and warfarintreated individuals by radioimmunoassay. Blood 1983; 62: 784-91.
    PubMedGoogle Scholar
  • 2 Peterson LC, Hedner U, Wildgoose P. Factor VII. In: High KA, Roberts HR. eds. Molecular Basis of Thrombosis and Hemostasis. New York, NY: Marcel Dekker, Inc; 1995: 147-65.
    Google Scholar
  • 3 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 02: 533-7.
    PubMedGoogle Scholar
  • 4 Tracy RP, Bovill EG, Yanez D, Psaty BM, Fried LP, Heiss G, Lee M, Polak JF, Savage PJ. Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study. Arterioscl Thromb 1995; 15: 1269-79.
    CrossrefPubMedGoogle Scholar
  • 5 de Maat MP, Green F, de Knijff P, Jespersen J, Kluft C. Factor VII polymorphisms in populations with different risks of cardiovascular disease. Arterioscl Thromb 1997; 17: 1918-23.
    CrossrefPubMedGoogle Scholar
  • 6 Iacoviello L, Di Castelnuovo A, De Knijff P, D’Orazio A, Amore C, Arboretti R, Kluft C, Benedetta MDonati. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998; 338: 79-85.
    CrossrefPubMedGoogle Scholar
  • 7 Girelli D, Russo C, Ferraresi P, Olivieri O, Pinotti M, Friso S, Manzato F, Mazzucco A, Bernardi F, Corrocher RP. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med 2000; 343: 774-80.
    CrossrefPubMedGoogle Scholar
  • 8 Lievers KJ, Mennen LI, Rattink AP, Zwinderman AH, Jukema JW, Schouten EG, deMaat MP. The -323Ins10 polymorphism for factor VII is not associated with coronary atherosclerosis in symptomatic men. The REGRESS study group. Thrombos Res 2000; 97: 275-80.
    CrossrefPubMedGoogle Scholar
  • 9 Doggen CJ, Manger VCats, Bertina RM, Reitsma PH, Vandenbroucke JP, Rosendaal FR. A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men. Thromb Haemost 1998; 80: 281-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Nederhand RJ, de Maat MP, Jukema JW. Regression Growth Evaluation Statin Study group. Factor VII polymorphisms and myocardial infarction: what is special in Italians? REGRESS study group. Regression Growth Evaluation Statin Study. Thromb Haemost 2001; 85: 746-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Bernardi F, Marchetti G, Pinotti M, Arcieri P, Baroncini C, Papacchini M, Zepponi E, Ursicino N, Chiarotti F, Mariani G. Factor VII gene polymorphisms contribute about one third of the factor VII level variation in plasma. Arterioscl Thromb 1996; 16: 72-6.
    PubMedGoogle Scholar
  • 12 Bladbjerg EM, Tholstrup T, Marckmann P, Sandstrom B, Jespersen J. Dietary changes in fasting levels of factor VII coagulant activity (FVII:C) are accompanied by changes in factor VII protein and other vitamin Kdependent proteins. Thromb Haemost 1995; 73: 239-42.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 de Valk-de Roo GW, Stehouwer CD, Emeis JJ, Nicolaas-Merkus A, Netelenbos C. Unopposed estrogen increases total plasma factor VII, but not active factor VII – a short-term placebo-controlled study in healthy postmenopausal women. Thromb Haemost 2000; 84: 968-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Pollak ES, Hung HL, Godin W, Overton GC, High KA. Functional characterization of the human factor VII 5’-flanking region. J Biol Chem 1996; 271: 1738-47.
    CrossrefPubMedGoogle Scholar
  • 15 Pinotti M, Toso R, Girelli D, Bindini D, Ferraresi P, Papa ML, Corrocher R, Marchetti G, Bernardi F. Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies. Blood 2000; 95: 3423-8.
    PubMedGoogle Scholar
  • 16 Hunault M, Arbini AA, Lopaciuk S, Carew JA, Bauer KA. The Arg353Gln polymorphism reduces the level of coagulation factor VII. In vivo and in vitro studies. Arterioscl Thromb 1997; 17: 2825-9.
    CrossrefPubMedGoogle Scholar
  • 17 Humphries S, Temple A, Lane A, Green F, Cooper J, Miller G. Low plasma levels of factor VIIc and antigen are more strongly associated with the 10 base pair promoter (-323) insertion than the glutamine 353 variant. Thromb Haemost 1996; 75: 567-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Marchetti G, Patracchini P, Papacchini M, Ferrati M, Bernardi F. A polymorphism in the 5’region of coagulation factor VII gene (F7) caused by an inserted decanucleotide. Hum Genet 1993; 90: 575-6.
    PubMedGoogle Scholar
  • 19 Bernardi F, Arcieri P, Bertina RM, Chiarotti F, Corral J, Pinotti M, Prydz H, Samama M, Sandset PM, Strom R, Garcia VV, Mariani G. Contribution of factor VII genotype to activated FVII levels. Differences in genotype frequencies between northern and southern European populations. Arterioscl Thromb 1997; 17: 2548-53.
    CrossrefPubMedGoogle Scholar
  • 20 Sacchi E, Tagliabue L, Scoglio R, Baroncini C, Coppola R, Bernardi F, Mannucci PM. Plasma factor VII levels are influenced by a polymorphism in the promoter region of the FVII gene. Blood Coagul Fibrinolysis 1996; 72: 114-7.
    PubMedGoogle Scholar
  • 21 Dell’Acqua G, Iacoviello L, D’Orazio A, Di Bitondo R, Di Castelnuovo A, Donati MB. A polymorphic cluster in the 5’region of the human coagulation factor VII gene: detection, frequency, and linkage disequilibrium. Thromb Res 1997; 88: 445-8.
    CrossrefPubMedGoogle Scholar
  • 22 van’t Hooft FM, Silveira A, Tornvall P, Iliadou A, Ehrenborg E, Eriksson P, Hamsten A. Two common functional polymorphisms in the promoter region of the coagulation factor VII gene determining plasma factor VII activity and mass concentration. Blood 1999; 93: 3432-41.
    PubMedGoogle Scholar
  • 23 Selden RF, Howie KB, Rowe ME, Goodman HM, Moore DD. Human growth hormone as a reporter gene in regulation studies employing transient gene expression. Mol Cell Biol 1986; 06: 3173-9.
    CrossrefPubMedGoogle Scholar
  • 24 Uyttersprot N, Costagliola S, Miot F. A new tool for efficient transfection of dog and human thymocytes in primary culture. Mol Cell Endo 1998; 142: 35-9.
    CrossrefPubMedGoogle Scholar
  • 25 Laposata M, Connor AM, Hicks DG, Phillips DK. The Clinical Hemostasis Handbook. Chicago, IL: Year Book Medical Publishers, Inc; 1989: 37.
  • 26 Arbini AA, Bodkin D, Lopaciuk S, Bauer KA. Molecular analysis of Polish patients with Factor VII deficiency. Blood 1994; 84: 2214-20.
    PubMedGoogle Scholar
  • 27 Gilles PN, Wu DJ, Foster CB, Dillon PJ, Chanock SJ. Single nucleotide polymorphic discrimination by an electronic dot blot assay on semiconductor microchips. Nat Biotechnol 1999; 17: 365-70.
    CrossrefPubMedGoogle Scholar
  • 28 Page GP, Amos CI. Comparison of linkage-disequilibrium methods for localization of genes influencing quantitative traits in humans. Am J Hum Genet 1999; 64: 1194-205.
    CrossrefPubMedGoogle Scholar
  • 29 Temple A, Luong LA, Cruickshank K, Humphries SE. The 10-base-pair insertion in the promoter of the factor VII gene is not associated with lower levels of factor VIIc in Afrocarribeans. Thromb Haemost 1997; 77: 213-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Peyvandi F, Mannucci P, Bucciarelli P, Zeinali S, Akhavan S, Sacchi E, Merlini PA. Perry DJ A novel polymorphism in intron 1a of the human factor VII gene (G73A): study of a healthy Italian population and of 190 young survivors of myocardial infarction. Br J Haematol 2000; 108: 247-53.
    CrossrefPubMedGoogle Scholar
  • 31 Arbini AA, Pollak ES, Bayleran JK, High KA, Bauer KA. Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in the factor VII promoter. Blood 1997; 89: 176-82.
    PubMedGoogle Scholar
  • 32 Carew JA, Pollak ES, Lopaciuk S, Bauer KA. A new mutation in the HNF4 binding region of the factor VII promoter in a patient with severe factor VII deficiency. Blood 2000; 96: 4370-2.
    PubMedGoogle Scholar
  • 33 Tidd T, Kudaravalli R, Beaverson K, DiMichele DM, High KA, Pollak ES. Two novel point mutations identified in the human coagulant protein Factor VII gene. Thromb Haemost Suppl 1999; 467: 1476.
    PubMedGoogle Scholar
  • 34 Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma PH. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscl Thromb 1995; 15: 214-8.
    CrossrefPubMedGoogle Scholar