© 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
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