Fibrinogen Aα-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism

doi:10.1016/j.thromres.2007.05.003

Thrombosis Research

Volume 121, Issue 3, 2007, Pages 333-338

https://doi.org/10.1016/j.thromres.2007.05.003 Get rights and content

Abstract

Introduction

Fibrinogen Aα-Thr312Ala and Factor XIII Val34Leu polymorphisms have been shown to modify fibrin clot structure and function. However, clinical studies have yielded conflicting results on their possible association with venous thromboembolism (VTE).

Methods

We studied the association between these two polymorphisms and VTE in a hospital-based case–control study. We also assessed whether an independent or interactive association exists between Aα-fibrinogen Thr312Ala and FXIII Val34Leu polymorphisms and VTE. Fibrinogen Aα-Thr312Ala and FXIII Val34Leu polymorphisms were determined after PCR and restriction endonuclease digestion in 286 patients with idiopathic VTE and 286 age- and gender-matched controls. Results were analysed using a conditional logistic regression model for matched series.

Results

The Fg-Aα 312Ala allele was associated with higher risk of VTE (OR 1.5; 95% CI: 1.1 to 2.2, p=0.01) while the FXIII 34Leu allele appeared protective (OR 0.7; 95% CI: 0.6 to 0.9, p=0.02). Both alleles demonstrated an independent association with idiopathic VTE after adjustment for Factor V Leiden and G20210A prothrombin polymorphisms. There was no interaction between the fibrinogen Aα-Thr312Ala and FXIII Val34Leu polymorphisms for the risk of VTE.

Conclusion

In this case-control study, the fibrinogen Fg-Aα 312Ala allele was associated with an increased risk of VTE. The FXIII 34Leu allele was also significantly associated with a lower risk of VTE without any interaction between the two polymorphisms studied.

Introduction

Venous thromboembolism (VTE) is a multifactor disease that frequently occurs when environmental factors interact with inherited risk factors. Among the most commonly recognized inherited risk factors, antithrombin, protein C, protein S deficiencies and factor V Leiden are associated with inadequate inhibition of thrombin generation, resulting in increased tendency to experience deep vein thrombosis. The G20210A variant of the prothrombin gene, also associated with an increased risk of thrombosis, is responsible for higher plasma concentrations of prothrombin, favouring thrombin generation and the formation of fibrin clots with a decreased mass-to-length ratio and thinner fibres that are more resistant to fibrinolysis [1]. Changes in fibrin clot structure could thus influence the susceptibility to develop venous thrombosis. In this regard, a common FXIII-A polymorphism, caused by a G to T point mutation in codon 34 of exon 2 of the FXIII-A subunit gene with a replacement of valine by leucine at position 34 (Val34Leu) in the activation peptide, has been consistently associated with increased activation of factor XIII by thrombin in vitro [2], [3]. The effect of this polymorphism on fibrin clot structure has not been fully defined, but the clots formed in the presence of 34Leu FXIII are thinner and less porous than those formed in the presence of wild type FXIII (34Val) and were shown to be relatively resistant to plasmin degradation [4]. Thus, the 34Leu FXIII-A allele should theoretically increase the risk of thrombosis. However clinical studies have demonstrated either no effect or a paradoxical protective effect [5], [6]. On the other hand, a coding polymorphism in the Aα gene of fibrinogen leading to a substitution of threonine by alanine at residue 312 of the Aα chain (Fg-Aα Thr312Ala) has been described. The Fg-Aα amino acid residue 312 is located in an area of the molecule close to the factor XIII cross-linking sites. This presumably explains why Ala312 fibrinogen has been shown to produce stiffer clots, associated with increased factor XIII-dependent α-chain cross-linking. In addition, Ala312 clots might be more exposed to fragmentation [7], [8] and the Fg-Aα Thr312Ala has been reported to be associated with pulmonary embolism in patients with deep vein thrombosis [9].

The aim of the present work was therefore to evaluate the association between fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms and idiopathic VTE in a hospital-based case–control study. We also investigated whether an independent or interactive association may exist between these two polymorphisms and VTE, and whether these associations are independent from factor V Leiden and G20210A prothrombin gene mutations.

Section snippets

Selection of patients and controls

Patients were recruited between May 2000 and December 2004, and included in the EDITH study if they had an objectively confirmed diagnosis of proximal deep vein thrombosis (DVT) or pulmonary embolism (PE). The ongoing EDITH project (Etude des Déterminants et Interactions de la THrombose veineuse) is a case–control study designed to test interactions between acquired and inherited risk factors for VTE [10].

All consecutive patients over the age of 18 years hospitalised in any unit of the

Results

300 pairs of matched cases and controls were selected and DNA was available for analyzing fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms in 286 of them. The mean age of patients was 66 years (standard deviation 17) and 52% were women.

The fibrinogen Aα Ala/Ala genotype was present in 8% of cases (23/286) and 9.1% of controls (26/286), the Ala/Thr genotype in 47.2% of cases (135/286) and 35.7% of controls (102/286) and the Thr/Thr genotype in 44.8% of cases (128/286) and 55.2% of

Discussion

In this case–control study, we found that the fibrinogen Aα-312Ala allele was associated with a 60% increased risk of idiopathic venous thromboembolism, whereas the factor XIII-A 34Leu allele was protective with a 30% reduced risk of VTE for each allele carried. These two polymorphisms did not interact within each other and their respective association with VTE was independent from factor V Leiden and prothrombin G20210A gene variation. In addition, no variation in these associations was found

Summary

This case–control study supports a positive and independent association between fibrinogen Aα-Thr312Ala polymorphism and VTE but without any specific relationship with the risk of pulmonary embolism. These data also confirm that the factor XIII 34Leu allele is independently associated with a reduced risk of VTE.

Acknowledgements

Authors are indebted to Mona Renault and Ghislaine Kermagoret for their help in gathering clinical and biological data. They also would like to thank Sylvie Henaf in Tours for her technical contribution, and all physicians and nurses in Brest who contributed to this study by identifying and including patients, and performing and managing blood samples, particularly J Cabon, L Gourant, MF Le Lay, L Le Roux, P Logeais, A Muniglia and AM Roguedas.

The EDITH study is partially funded by the “Projets

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The Ala allele of rs6050 increases FXIIIa-dependent fibrinogen alpha chain cross-linking and formation of thicker fibrin fibers, resulting in stiffer clots [28]. Several case-control studies have found a positive association between the Ala allele of rs6050 and risk of venous thromboembolism [29–31]. A GWAS and a small candidate gene association study in populations of European ancestry further demonstrated a positive association between the Ala allele of rs6050 and D-dimer levels [6,7].
D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.
We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.
Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0 × 10^− 6. The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer.
Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.
Chronic thromboembolic pulmonary hypertension
2013, Clinics in Chest Medicine
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The presence of abnormal fibrinogen types and failure to cleave fibrinogen by plasminogen is another possible explanation for incomplete clot resolution.24,38,39 The (Fg)-Aa Thr312Ala fibrinogen genotype has been identified in greater frequency in patients with CTEPH and is associated with increased risk of VTE.40,41 Fibrotic changes in pulmonary arteries can also contribute to vascular narrowing and occlusion.
Natural History of Venous Thromboembolism
2011, Critical Care Clinics
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Patients in whom VTE is manifested by PE tend to recur with PE rather than with DVT alone.38 A provocative finding in some of the patients with PE is the presence of a fibrinogen mutation,39–41 which gives rise to highly cross-linked, and therefore tightly compressed, thrombi.42 DVT arising in patients with the mutation may be predisposed to embolization.
Allele-allele interaction within the F13A1 gene: A risk factor for Ischaemic Heart Disease in Spanish population
2010, Thrombosis Research
Fibrinogen α and γ genes and factor V<sup>Leiden</sup> in children with thromboembolism: Results from 2 family-based association studies
2009, Blood
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Our present findings further show that the most frequent FGA-H1 haplotype is overrepresented in pediatric VT patients and in children with nonvascular stroke. In adults, the Ala312Thr polymorphism in FGA has been linked to VT19,21,22 and poststroke mortality in patients with atrial fibrillation.23 The FGA H1 haplotype is uniquely detected by the presence of the A-allele of the SNP rs6050, which encodes the Ala312 variant of the fibrinogen Aα chain, whereas the other 4 major FGA haplotypes are composed of the G-allele of rs6050, encoding the Thr312 Aα chain.
Previous case-control studies showed that genetic variation in the fibrinogen γ gene (FGG) increased the risk for deep vein thrombosis (VT) in adults. We investigated the association between the fibrinogen α (FGA) and FGG haplotypes, the factor V^Leiden-mutation, and pediatric VT and thromboembolic stroke (TS) in 2 independent study samples. Association analysis revealed that the FGA-H1 and FGG-H2 haplotypes were significantly overtransmitted to VT patients (FGA-H1, P = .05; FGG: H2, P = .032). In contrast, the FGG-H3 haplotype was undertransmitted (P = .022). In an independent study sample, FGA-H1 (P = .008) and FGG-H2 (P = .05) were significantly associated with TS. The association of FGA and FGG haplotypes with VT was more pronounced in FV^Leiden-negative families (FGA-H1, P = .001; FGG-H2, P = .001), indicating a genetic interaction between both risk factors. The risk-conferring FGG-H2 and the protective FGG-H3 haplotypes correlated with low (FGG-H2) and high (FGG-H3) levels of the γ′ chain variant, respectively. These results provide independent and novel evidence that FGA-H1 and FGG-H2 variants are associated with an increased risk of VT and TS in children. The observed negative correlation of genetic VT risk with the plasma levels of the fibrinogen γ′ variant suggests that FGG-H2 and -H3 haplotypes modify thrombosis risk by controlling the level of this FGG splice isoform.
Common genetic variants associated with plasma fibrin D-dimer concentration in older European- and African-American adults
2008, Journal of Thrombosis and Haemostasis
Background and Objectives: D‐dimer is a hemostasis marker that reflects ongoing fibrin formation and degradation. There is significant inter‐individual and inter‐population variability in D‐dimer concentration, but whether genetic factors underlie these differences is largely unknown. We hypothesized that common coagulation gene variants contribute to differences in circulating D‐dimer concentration. Methods: The setting was European‐American (EA; n=1858) and African‐American (AA; n=327) unrelated older adults from the Cardiovascular Health Study (CHS), in which we genotyped SNPs in 42 genes related to blood coagulation and fibrinolysis. Results: Several fibrinogen gene polymorphisms, including the Thr312Ala Aα chain variant and the FGG‐10034 C/T variant, were associated with ∼20% higher plasma D‐dimer levels in EA (false discovery rate < 5% for covariate‐adjusted model). There was also some evidence that a Pro41Leu variant of the PLAU gene encoding urinary plasminogen activator and non‐coding polymorphism of the plasminogen activator inhibitor type 1 gene (SERPINE1) were associated with higher plasma D‐dimer in EA. There were no significant associations between the studied coagulation or fibrinolysis gene SNPs and plasma D‐dimer levels in the smaller AA sample. However, each standard deviation increase in European ancestry assessed by ancestry‐informative gene markers was associated with ∼10% lower mean D‐dimer levels in AA. Conclusions: Together, common coagulation/fibrinolysis gene SNPs explained only ∼2% of the variance in plasma D‐dimer levels in EA. These findings suggest that the association of D‐dimer with risk of vascular outcomes may be mediated largely by environmental factors, other genes, and/or genetic interactions.

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^☆: GLG collected data, analyzed data and wrote the paper; BD performed research and wrote the paper; KL collected data; VM performed research; SR performed research; MTB collected data; FC collected data; DM designed research; EO designed research and collected data; YG designed research and wrote the paper.

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Regular articleFibrinogen Aα-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism☆

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Section snippets

Selection of patients and controls

Results

Discussion

Summary

Acknowledgements

Blood

Blood

Blood

Blood

J Thromb Haemost

Blood

Blood

Blood

Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A

Thromb Haemost

The FXIII Val 34 Leu mutation and the risk of venous thrombosis

Thromb Haemost

Regular article
Fibrinogen Aα-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism☆