REGULAR ARTICLEThe fibrinogen gamma (FGG) 10034C>T polymorphism is associated with venous thrombosis
Introduction
Deep venous thrombosis (DVT) is a multifactorial disease with both environmental and genetic factors contributing to its development [1], [2]. Elevated plasma fibrinogen concentrations have previously been associated with an increased risk for DVT [3], [4]. Fibrinogen is a 340 kDa plasma glycoprotein and consists of three pairs of non-identical polypeptide chains (Aα, Bβ, and γ), which are each encoded by a different gene (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]) [5], [6], [7], [8]. Thrombin-induced conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the thrombus. Furthermore, elevated plasma fibrinogen levels have been associated with both increased plasma viscosity and platelet aggregability [9], [10].
A haplotype-tagging single nucleotide polymorphism (htSNP) characterized by a C to T substitution at nucleotide 10034 of the FGG gene (FGG 10034C>T, rs2066865), has recently been proposed as a novel risk factor for DVT in the Leiden Thrombophilia Study [11]. The purpose of the present study was re-analyzed by the previously described association between the FGG 10034C>T polymorphism and DVT in an Austrian population.
Section snippets
Materials and methods
Three hundred and fifty eight subjects with a documented episode of DVT of the lower extremities, admitted to the Department of Internal Medicine, Medical University Graz, between December 1997 and June 2002, were enrolled as the patient group [12]. DVT was diagnosed by ultrasonography and/or venography. Pulmonary embolism (PE) was diagnosed by ventilation–perfusion scintigraphy and/or CT pulmonary angiography. Patients with isolated PE without diagnosis of DVT were not eligible.
A control group
Results
Characteristics of study subjects are summarized in Table 1. DVT was diagnosed as first event in 299 (83.5%) patients and recurrent event in 59 (16.5%) patients. FGG genotypes were determined successfully in 341 (95.3%) patients with DVT, 342 (96.6%) in-house controls and all population-based controls and did not deviate from the Hardy–Weinberg equilibrium among either group. Genotype distributions are summarized in Table 1.
Genotype frequencies were almost identical among in-house controls and
Discussion
In the present study, homozygous carriers of the FGG 10034T-allele were found more often in patients with DVT than among control subjects without thrombosis. Our result confirms the primary finding of Uitte de Willige and coworkers, who identified this genotype as a novel risk factor for DVT [11] (Fig. 1).
The precise mechanism by which this polymorphism affects susceptibility to DVT has only partially been determined. According to SeattleSNPs (http://pga.gs.washington.edu), the genetic
Acknowledgments
We thank Biomedical Scientists Manuela Gutjahr, Renate Jahrbacher and Olivia Trummer for helpful comments and critical evaluation of the manuscript.
References (15)
- et al.
High levels of fibrinogen are associated with risk of deep venous thrombosis mainly in the elderly
J Thromb Haemost
(2003) Fibrinogen and fibrin structure and function
J Thromb Haemost
(2005)Fibrinogen and fibrin structure and functions
J Thromb Haemost
(2005)- et al.
Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels
Blood
(2005) - et al.
The functional − 4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis
J Thromb Haemost
(2005) - et al.
Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria
Thromb Res
(2000) - et al.
Resistance of gammaA/gamma' fibrin clots to fibrinolysis
J Biol Chem
(1997)
Cited by (40)
Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities
2024, Journal of Thrombosis and HaemostasisVenous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: Linkage to ovarian tumour behaviour
2020, Biochimica et Biophysica Acta - Reviews on CancerProspective study of γ′ fibrinogen and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE)
2016, Thrombosis ResearchCitation Excerpt :Another study reported that the minor allele of the FGG single nucleotide polymorphism (SNP) rs1049636, which is associated with increased mean γ′ fibrinogen levels, is associated with decreased risk of VTE [7]. Supporting a potential etiological role for lower γ′ fibrinogen in increasing VTE risk, three [8–10] of five [8–12] genome-wide association studies (GWAS) and some candidate-gene studies [6,13–15] have linked SNPs in FGG to VTE risk in whites. Our GWAS consortium of VTE found the top FGG SNP to be rs6536024 [8], which is in modest linkage disequilibrium (r2 = 0.25–0.53) with FGG variants linked to VTE in other studies, namely, three tightly linked SNPs (rs7659024, rs2066865, and rs2066854, r2 = 1.0 among them) and rs1049636 [6,7,9,10,13–15].
The contribution of genetic and environmental factors to changes in total and γ' fibrinogen over 5 years
2015, Thrombosis ResearchCitation Excerpt :The reason for this decrease is possibly due to the polymorphism’s location in a cleavage stimulatory factor (CstF) consensus 2a sequence close to the polyadenylation site of the fibrinogen γA exon 10 [35,36]. Therefore, the mutant allele of the SNP at rs2066865 could be responsible for the production of more fibrinogen γA and less fibrinogen γ’ [35,36]. The polymorphism at rs1049636 with HbA1c and time interaction was the only significant gene-environment interaction that affected total fibrinogen concentration over the five-year period.
Neurologic Manifestations of Hematologic Disorders
2014, Aminoff's Neurology and General Medicine: Fifth Edition
- 1
These authors contributed equally to the study.