Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Willige, Shirley Uitte de; Visser, Marieke C.; Houwing-Duistermaat, Jeanine J.; Rosendaal, Frits R.; Vos, Hans L.; Bertina, Rogier M.

doi:10.1182/blood-2005-05-2180

Cited by 220 publications

(283 citation statements)

References 62 publications

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“…In particular, a decrease of this chain was associated with a net increase of the risk factor for venous thromboembolism (6). In contrast, as anticipated above, the role of this fibrinogen chain for arterial thrombosis is still debated (6,7,13). Clinical studies were conducted in the attempt to demonstrate whether altered levels of ␥Ј chain are inversely or directly correlated with increased risk for arterial thrombosis.…”

Section: Discussionmentioning

confidence: 98%

“…The influence of ␥Ј chain on venous thrombosis has been largely recognized (6). In particular, a decrease of this chain was associated with a net increase of the risk factor for venous thromboembolism (6).…”

Section: Discussionmentioning

confidence: 99%

“…The inserted region at the C terminus is composed of 20 (5). The elongated ␥ chain, termed ␥Ј, mainly heterodimerizes in the fibrinogen molecule with the more abundant ␥A chain, thus generating the ␥A/␥Ј dimers (6). This fibrinogen, also called ␥A/␥Ј fibrinogen, shows a high inter-individual variability in the ratio to the total fibrinogen ␥ chain (7).…”

mentioning

confidence: 99%

“…This haplotype is associated with a significantly increased risk for venous thrombosis (6). Biochemical studies showed that ␥Ј chains bind to ␣-thrombin with high affinity (8) and that the 408 -427 region of ␥Ј chain binds to the anion-binding exosite (ABE) 2 -II of thrombin (1,9).…”

mentioning

confidence: 99%

“…At variance with venous thromboembolism, the significance of altered expression of ␥Ј chain on arterial thrombosis remains largely elusive (6,7,12,13). Platelets are major players of arterial thrombus formation, as also demonstrated by the clinical efficacy of anti-platelet agents in cardiovascular prevention.…”

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confidence: 99%

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Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Lancellotti

Rutella

Filippis

et al. 2008

Journal of Biological Chemistry

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The expression of the elongated fibrinogen ␥ chain, termed ␥, derives from alternative splicing of mRNA and causes an insertion sequence of 20 amino acids. This insertion domain interacts with the anion-binding exosite (ABE)-II of thrombin. This study investigated whether and how ␥ chain binding to ABE-II affects thrombin interaction with its platelet receptors, i.e. glycoprotein Ib␣ (GpIb␣), protease-activated receptor (PAR) 1, and PAR4. Both synthetic ␥ peptide and fibrinogen fragment D*, containing the elongated ␥ chain, inhibited thrombin-induced platelet aggregation up to 70%, with IC 50 values of 42 ؎ 3.5 and 0.47 ؎ 0.03 M, respectively. Solid-phase binding and spectrofluorimetric assays showed that both fragment D* and the synthetic ␥ peptide specifically bind to thrombin ABE-II and competitively inhibit the thrombin binding to GpIb␣ with a mean K i ≈ 0.5 and ≈35 M, respectively. Both these ␥ chain-containing ligands allosterically inhibited thrombin cleavage of a synthetic PAR1 peptide, of native PAR1 molecules on intact platelets, and of the synthetic chromogenic peptide D-Phe-pipecolyl-Arg-p-nitroanilide. PAR4 cleavage was unaffected. In summary, fibrinogen ␥ chain binds with high affinity to thrombin and inhibits with combined mechanisms the platelet response to thrombin. Thus, its variations in vivo may affect the hemostatic balance in arterial circulation.Fibrinogen is a key molecule in both primary and secondary hemostasis, because of its role in forming the platelet plug by connecting activated platelets and in forming plasma fibrin clot upon thrombin cleavage. Fibrinogen consists of two symmetric half-molecules, each containing a set of three different polypeptide chains termed A␣, B␤, and ␥. The latter contains several sites that interact with different ligands such as other fibrin(ogen) molecules, coagulation enzymes, growth factors, and integrins (1). The product of thrombin digestion of fibrinogen, i.e. fibrin, binds with a considerable specificity thrombin, so that in the early studies fibrin was termed antithrombin I (2). Thrombin has a divalent interaction with two classes of binding sites on fibrin, one of low affinity in the E domain and the other of high affinity in the D domain of fibrin(ogen) molecules (3). Binding of thrombin to fibrinogen involves sequences of both A␣ and B␤ chain, which contain recognition sites in the fibrinogen E domain. These recognition sites are still able to interact with thrombin after cleavage of fibrinopeptide A and B and form the low affinity binding site for the enzyme. The D domains contain a ␥ chain variant, termed ␥Ј, arising from an alternative mRNA splicing (4), resulting in an elongated chain composed of 427 instead of 411 residues. The inserted region at the C terminus is composed of 20 amino acids ( 408 VRPEH-PAETEYDSLYPEDDL 427 ), rich of acidic side chains and two sulfate anions linked to Tyr 418 and Tyr 422 (5). The elongated ␥ chain, termed ␥Ј, mainly heterodimerizes in the fibrinogen molecule with the more abundant ␥A chain, thus generating ...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Lancellotti

Rutella

Filippis

et al. 2008

Journal of Biological Chemistry

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Association of Genetic Variations With Nonfatal Venous Thrombosis in Postmenopausal Women

Smith¹,

Hindorff²,

Heckbert³

et al. 2007

JAMA

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178

181

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Context Although the roles of clotting proteins and enzymes that activate or inhibit fibrin production and lysis are well characterized, the underlying contribution of genetic variation in these constituents to risk of venous thrombosis (VT) has not been fully investigated.Objective To describe the association of common genetic variation in 24 coagulation, anticoagulation, fibrinolysis, and antifibrinolysis candidate genes with risk of incident nonfatal VT in postmenopausal women.Design, Setting, and Participants Population-based case-control study conducted in a large integrated health care system in Washington State. Participants were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first VT event between January 1995 and December 2002 (n=349) and 1680 controls matched on age, hypertension status, and calendar year (n=1680).Main Outcome Measure Risk of venous thrombosis associated with global variation within a gene as measured by common haplotypes and with individual haplotypes and single nucleotide polymorphisms (SNPs). Significance of the associations was assessed by a .20 threshold of the false-discovery rate q value, which accounts for multiple testing. ResultsOnly the tissue factor pathway inhibitor gene demonstrated global association with risk (q = .13). Five significant SNP associations were identified across 3 of the candidate genes (factors V, XI, and protein C) in SNP analyses. Two associations have been previously reported. Another 22 variants across 15 genes had P values less than .05 but q values between .20 and .35. Five of these confirm previously reported associations (fibrinogen genes and protein C), 2 were inconsistent with earlier reports (thrombomodulin and plasminogen activator inhibitor 1), and 15 were new discoveries. ConclusionsAfter accounting for multiple testing, 5 SNPs associated with VT risk were identified, 3 of which have not been previously reported. Replication of these novel associations in other populations is necessary to corroborate these findings and identify which genetic factors may influence VT risk in postmenopausal women.

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A Genome‐Wide Association Study for Venous Thromboembolism: The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Tang

Teichert

Chasman

et al. 2013

Genetic Epidemiology

101

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Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a 2-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended CHARGE VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to ~2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (p≤0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG) (p<5.0×10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (p<5.0×10-6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

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Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Cited by 220 publications

References 62 publications

Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Association of Genetic Variations With Nonfatal Venous Thrombosis in Postmenopausal Women

A Genome‐Wide Association Study for Venous Thromboembolism: The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

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