© 1999 American Heart Association, Inc.
Thrombosis |
Two Common, Functional Polymorphisms in the Promoter Region of the ß-Fibrinogen Gene Contribute to Regulation of Plasma Fibrinogen Concentration
From the Atherosclerosis Research Unit (F.M.v.H., S.J.F.v.B., A.S., P.E., A.H.), King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, and the Division of Genetic Epidemiology (A.I.), Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
Correspondence to Dr Ferdinand M. van ’t Hooft, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Abstract—Plasma fibrinogen is a
major risk factor for coronary heart disease, stroke, and
peripheral artery disease. There is evidence that genetic
variation in the ß-fibrinogen gene contributes to the rate of
synthesis of fibrinogen, but the molecular mechanism underlying the
genetic heritability of the plasma fibrinogen concentration is largely
unknown. We evaluated the physiological roles of 5
common nucleotide substitutions in the promoter region of
the ß-fibrinogen gene at positions -148, -249, -455, -854, and
-993 from the transcriptional start site. Electrophoretic mobility
shift assays revealed distinct differences in the binding
characteristics of nuclear proteins between wild-type and mutant
fragments of both the -455G/A and -854G/A polymorphisms, whereas
no clear differences were observed for the -148C/T, -249C/T, and
-993C/T sites. Transfection studies in HepG2 cells showed increased
basal rates of transcription for both the G-to-A substitution at
position -455 (+50%, P<0.05) and the G-to-A
substitution at -854 (+51%, P<0.05). Additional
transfection studies using proximal promoter constructs confirmed that
both the -455A and -854A alleles independently enhance the basal
rate of transcription of the ß-fibrinogen gene. The rare alleles
of the nonrelated -455G/A and -854G/A polymorphisms were also
associated with significantly increased plasma fibrinogen levels in
healthy middle-aged men. Overall, the 2 polymorphisms together
explained 
11% of the variation in plasma fibrinogen concentration.
It is concluded that the -455G/A and -854G/A polymorphisms of the
ß-fibrinogen gene are physiologically
relevant mutations with a significant impact on the plasma
fibrinogen concentration.
Key Words: DNA • fibrinogen • ß-fibrinogen gene • -455G/A polymorphism • -845G/A polymorphism
This article has been cited by other articles:
 |
|
 |
|
  B. Jacquemin, C. Antoniades, F. Nyberg, E. Plana, M. Muller, S. Greven, V. Salomaa, J. Sunyer, T. Bellander, A.-G. Chalamandaris, et al. Common Genetic Polymorphisms and Haplotypes of Fibrinogen Alpha, Beta, and Gamma Chains Affect Fibrinogen Levels and the Response to Proinflammatory Stimulation in Myocardial Infarction Survivors: The AIRGENE Study J. Am. Coll. Cardiol., September 9, 2008; 52(11): 941 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Koch, P. Hoppmann, J. Biele, J. C. Mueller, A. Schomig, and A. Kastrati Fibrinogen Genes and Myocardial Infarction: A Haplotype Analysis Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 758 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Michienzi, N. Cherman, K. Holmbeck, A. Funari, M. T. Collins, P. Bianco, P. G. Robey, and M. Riminucci GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs{alpha} Hum. Mol. Genet., August 15, 2007; 16(16): 1921 - 1930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Keavney, J. Danesh, S. Parish, A. Palmer, S. Clark, L. Youngman, M. Delepine, M. Lathrop, R. Peto, R. Collins, et al. Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization' Int. J. Epidemiol., August 1, 2006; 35(4): 935 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pajala, P. Era, M. Koskenvuo, J. Kaprio, M. Alen, A. Tolvanen, K. Tiainen, and T. Rantanen Contribution of Genetic and Environmental Factors to Individual Differences in Maximal Walking Speed With and Without Second Task in Older Women J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2005; 60(10): 1299 - 1303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Verschuur, M. de Jong, L. Felida, M. P. M. de Maat, and H. L. Vos A Hepatocyte Nuclear Factor-3 Site in the Fibrinogen {beta} Promoter Is Important for Interleukin 6-induced Expression, and Its Activity Is Influenced by the Adjacent -148C/T Polymorphism J. Biol. Chem., April 29, 2005; 280(17): 16763 - 16771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xia Regulation of {gamma}-Fibrinogen Chain Expression by Heterogeneous Nuclear Ribonucleoprotein A1 J. Biol. Chem., April 1, 2005; 280(13): 13171 - 13178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M P J van Goor, E B Gomez-Garcia, F W G Leebeek, G J Brouwers, P J Koudstaal, and D W J Dippel The - 148 C/T fibrinogen gene polymorphism and fibrinogen levels in ischaemic stroke: a case-control study J. Neurol. Neurosurg. Psychiatry, January 1, 2005; 76(1): 121 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Vanschoonbeek, M. A.H. Feijge, M. Paquay, J. Rosing, W. Saris, C. Kluft, P. L.A. Giesen, M. P.M. de Maat, and J. W.M. Heemskerk Variable Hypocoagulant Effect of Fish Oil Intake in Humans: Modulation of Fibrinogen Level and Thrombin Generation Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1734 - 1740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Kamath and G.Y.H. Lip Fibrinogen: biochemistry, epidemiology and determinants QJM, October 1, 2003; 96(10): 711 - 729. [Full Text] [PDF]
|
|
|
|
|
|
S. Hutchinson, A. Furger, D. Halliday, D. P. Judge, A. Jefferson, H. C. Dietz, H. Firth, and P. A. Handford Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype? Hum. Mol. Genet., September 15, 2003; 12(18): 2269 - 2276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Klein, S. J. Hunter, A. J. Jenkins, D. Zheng, A. J. Semler, J. Clore, W. T. Garvey, and The DCCT/EDIC Study Group Fibrinogen Is a Marker for Nephropathy and Peripheral Vascular Disease in Type 1 Diabetes: Studies of plasma fibrinogen and fibrinogen gene polymorphism in the DCCT/EDIC cohort Diabetes Care, May 1, 2003; 26(5): 1439 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Martiskainen, T. Pohjasvaara, J. Mikkelsson, R. Mantyla, T. Kunnas, P. Laippala, E. Ilveskoski, M. Kaste, P.J. Karhunen, and T. Erkinjuntti Fibrinogen Gene Promoter -455 A Allele as a Risk Factor for Lacunar Stroke Stroke, April 1, 2003; 34(4): 886 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Athan, J. H. Lee, A. Arriaga, R. P. Mayeux, and B. Tycko Polymorphisms in the Promoter of the Human APP Gene: Functional Evaluation and Allele Frequencies in Alzheimer Disease Arch Neurol, November 1, 2002; 59(11): 1793 - 1799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Freeman, M. W. Mansfield, J. H. Barrett, and P. J. Grant Genetic Contribution to Circulating Levels of Hemostatic Factors in Healthy Families With Effects of Known Genetic Polymorphisms on Heritability Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 506 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.A. Laffan Fibrinogen polymorphisms and disease Eur. Heart J., December 2, 2001; 22(24): 2224 - 2226. [PDF]
|
|
|
|
|
|
G.J. Blake, C. Schmitz, K. Lindpaintner, and P.M. Ridker Mutation in the promoter region of the {beta}-fibrinogen gene and the risk of future myocardial infarction, stroke and venous thrombosis Eur. Heart J., December 2, 2001; 22(24): 2262 - 2266. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Iacoviello, M. Vischetti, F. Zito, and M. Benedetta Donati Genes Encoding Fibrinogen and Cardiovascular Risk Hypertension, November 1, 2001; 38(5): 1199 - 1203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y Liu, N Saha, C K Heng, S Hong, and P S Low Fibrinogen genotypes ({alpha} and {beta}) are associated with plasma fibrinogen levels in Chinese J. Med. Genet., September 1, 2001; 38(9): e31 - 31. [Full Text] [PDF]
|
|