Genetic variation in fibrinogen; its relationship to fibrinogen  levels and the risk of myocardial infarction and ischemic stroke.
BACKGROUND
Confounding by common causes and reverse causation have been proposed as explanations for the association between high fibrinogen levels and cardiovascular disease. Genetic variants can alter fibrinogen characteristics and are not subject to these problems.


OBJECTIVE
To determine the fibrinogen plasma levels for genotypic variants in fibrinogen-A alpha (FGA Thr312Ala) and fibrinogen-B beta (FGB - 455G/A), and whether these variants are associated with arterial thrombosis.


METHODS
Fibrinogen genotypes were determined in a population-based case-control study including women aged 18-50 years; 218 cases with myocardial infarction, 192 cases with ischemic stroke, and 769 healthy controls. Fibrinogen levels were determined in the control population.


RESULTS
The FGB - 455G/A variant increased plasma fibrinogen levels, whereas the FGA Thr312Ala variant lowered plasma fibrinogen levels, albeit to a modest extent. The risk of ischemic stroke was altered when the homozygote minor allele was compared with the homozygote major allele. The FGA Thr312Ala single-nucleotide polymorphism (SNP) was associated with a decrease in risk [odds ratio (OR) 0.43; 95% confidence interval (CI) 0.21-0.87], whereas the FGB - 455G/A SNP might have increased the risk (OR 1.76; 95% CI 0.7-4.03). The risk of myocardial infarction was not altered for either SNP (FGA Thr312Ala, OR 0.98, 95% CI 0.40-2.40; FGB - 455G/A, OR 0.98, 95% CI 0.40-2.40).


CONCLUSIONS
With the genetic variations as markers of plasma fibrinogen levels alterations, thereby ruling out confounding and reverse causation, our results suggest that plasma fibrinogen levels could play a more pronounced role as risk factors for ischemic stroke than for myocardial infarction.
Siegerink
B
B
Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands.
Rosendaal
F R
FR
Algra
A
A
D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005340:Fibrinogen / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D020521:Stroke / Q000209:etiology / Q000235:genetics*; D013927:Thrombosis / Q000209:etiology / Q000235:genetics
D005340:Fibrinogen