Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels.
We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen gamma' (gammaA/gamma' plus gamma'/gamma') levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen gamma' levels and reduced ratios of fibrinogen gamma' to total fibrinogen. Multivariate analysis showed that reduced fibrinogen gamma' levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen gamma' to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5). We propose that FGG-H2 influences thrombosis risk through htSNP 10034C/T [rs2066865] by strengthening the consensus of a CstF site and thus favoring the formation of gammaA chain above that of gamma' chain. Fibrinogen gamma' contains a unique high-affinity, nonsubstrate binding site for thrombin, which seems critical for the expression of the antithrombin activity that develops during fibrin formation (antithrombin 1).
Uitte de Willige
Shirley
S
Hemostasis and Thrombosis Research Center, Department of Hematology (C2-R), Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
de Visser
Marieke C H
MC
Houwing-Duistermaat
Jeanine J
JJ
Rosendaal
Frits R
FR
Vos
Hans L
HL
Bertina
Rogier M
RM
D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D012307:Risk Factors; D020246:Venous Thrombosis / Q000097:blood* / Q000235:genetics* / Q000473:pathology
D005340:Fibrinogen