Factor XIII Val34Leu variant and the risk of myocardial infarction

Shafey, Mona; Anderson, J; Scarvelis, Dimitrios; Doucette, Steven; Gagnon, France; Wells, Philip S.

doi:10.1160/th06-09-0517

Cited by 33 publications

(20 citation statements)

References 31 publications

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“…5 However, the Leu34 allele of the FXIII Val34Leu polymorphism was associated with slightly prolonged lysis times. This latter result conflicts with the reported protective effect of Leu34, 26,27 while supporting results of a recent study showing less effective thrombolytic therapy after acute MI in subjects possessing Leu34. 28 We have previously reported that Val34Leu demonstrates complex interactions with other genes and metabolic variables, 29,30 therefore further work is required to understand the mechanisms responsible for these observations and the implications for fibrinolytic therapy.…”

Section: Discussioncontrasting

confidence: 81%

Heritability of Clot Formation, Morphology, and Lysis

Carter

Cymbalista

Spector

et al. 2007

ATVB

157

152

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Objective-The relative balance between clot formation and fibrinolysis is considered to reflect thrombotic potential following vascular injury. The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study, and (2) Key Words: heritability Ⅲ coagulation Ⅲ fibrinolysis Ⅲ metabolic syndrome Ⅲ cardiovascular disease T he development of cardiovascular disease (CVD) is associated with a major thrombotic component initiated by underlying vascular damage. In occlusive arterial disease the development of a platelet rich thrombus is supported by a fibrin mesh, with fibrin formation dependent on complex interactions between components of the coagulation cascade. A significant contribution of additive genetic factors in determining risk for thrombosis was indicated by the GAIT Study, in which genetic factors accounted for Ϸ60% of variation in risk. 1 All the genes encoding hemostatic factors are potential candidates for thrombosis and studies in families and twins have demonstrated significant contributions of additive genetic factors to variance in these intermediate phenotypes. [2][3][4][5][6][7][8][9] Significant genetic correlations between hemostatic factors and thrombosis were identified in the GAIT study, indicating shared genes regulate plasma levels of hemostatic factors and susceptibility to thrombosis. 1 Although genetic factors contribute to variance in hemostatic factors, associations between common genetic variants of the genes encoding a variety of hemostatic components and CVD have generally been inconsistent. 10 Clot formation and fibrinolysis are dynamic processes, and identification of genetic factors regulating individual hemostatic factors may be less informative in relation to cardiovascular risk than identifying genetic factors influencing more complex phenotypes reflecting fibrin structure/function. A study in twins indicated heritabilities of 0.39 and 0.46 for clot permeability and clot density, 11 suggesting that genetic factors are important determinants of these phenotypes.The limited studies which have evaluated fibrin clot structure/function in relation to CVD indicate that dense structures, with increased stiffness, decreased permeability, and decreased clot lysis are observed in subjects with CVD 12,13 and in relatives of individuals with CVD. 14 Further understanding of the genetic and environmental determinants of fibrin structure/function may help to identify novel factors which influence vascular risk, and, in the longer term, inform the development of novel therapeutics.The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study and (2) to determine the relationship between measures of clot structure/function and the metabolic syndrome as an indicator of cardiovascular risk.

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Section: Discussioncontrasting

confidence: 81%

Heritability of Clot Formation, Morphology, and Lysis

Carter

Cymbalista

Spector

et al. 2007

ATVB

157

152

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“…The Leu allele of the F13A1 Val34Leu variant (Ref SNP ID no. : rs5985) increases the rate of FXIII activation and alters fibrin clot structure, 11 and has been associated with a decreased risk of myocardial infarction 12 and ischemic stroke. 13 The Phe allele of the F13A1 Tyr204Phe variant (rs3024477) lowers both FXIII plasma level 14 and FXIII activity, 15 and slightly increased the risk of ischemic stroke in young women in 1 study.…”

Section: Introductionmentioning

confidence: 99%

Coagulation factor XIII gene variation, oral contraceptives, and risk of ischemic stroke

Pruissen

Slooter

Rosendaal

et al. 2008

Blood

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Prothrombotic conditions are associated with ischemic stroke in young women. In particular, the combination of oral contraceptive use and prothrombotic genetic variants appears to increase the risk of ischemic stroke. We performed a population-based case-control study in 190 women aged 20 to 49 years with ischemic stroke and 767 women without cardiovascular disease stratified for age, calendar year of the index event, and residence. A total of 4 variants of coagulation factor XIII subunit A and B genes (F13A1 and F13B) were investigated. The Phe allele of the F13A1 Tyr204Phe variant was present in 59 (31%) patients and 43 (6%) controls; the odds ratio for ischemic stroke was 9.1 for Phe/Phe and Phe/Tyr versus Tyr/Tyr genotype; the 95% confidence interval was 5.5 to 15. Homozygous genotypes (Phe/Phe) conferred a higher risk (odds ratio, 77; 95% confidence interval, 7.0-848) than heterozygous (Tyr/Phe) genotypes (odds ratio, 8.2; 95% confidence interval, 4.9-14). The risk of ischemic stroke was further increased in carriers of the 204Phe allele using oral contraceptives (odds ratio, 20; 95% confidence interval, 9-46) compared with nonusers with Tyr/Tyr genotype. In conclusion, the F13A1 204Phe allele was strongly associated with ischemic stroke in young women. Oral contraceptive use further increased the risk of ischemic stroke. IntroductionProthrombotic conditions are associated with ischemic stroke in young women. For example, oral contraceptive use approximately doubles the risk of ischemic stroke. 1 Genetic factors also appear to play a role as is indicated by familial aggregation of ischemic stroke in young women. 2 Two prothrombotic genetic variants, the prothrombin G20210A variant and the methylenetetrahydrofolate (MTHFR) C677T variant, have been associated with ischemic stroke in young women. 3 Previous studies also found evidence of a combined effect of oral contraceptive use and prothrombotic gene variation on ischemic stroke risk. [3][4][5][6] Coagulation factor XIII (FXIII) is a protransglutaminase that circulates as a heterotetramer composed of 2 A and 2 B subunits. Activated FXIII is involved in cross-linking of the fibrin clot by transglutaminase reactions between glutamine and lysine residues on fibrin. The effect of a specific change in FXIII plasma level or activity on clot structure and thrombotic risk appears to depend upon several other factors, including the concentrations of thrombin, prothrombin, fibrinogen, and fibronectin. 7-9 A twin study showed a clear genetic influence on fibrin clot structure. 10 Several variants in the FXIII subunit A and B genes (F13A1 and F13B) change the FXIII level or activity and may therefore affect clot structure and the risk of thrombotic disease. Some of these variants have also been previously associated with myocardial infarction or ischemic stroke. The Leu allele of the F13A1 Val34Leu variant (Ref SNP ID no.: rs5985) increases the rate of FXIII activation and alters fibrin clot structure, 11 and has been associated with a decreased risk of myocardial in...

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“…190,191 Two meta-analyses both suggest that the FXIII-A Val34Leu polymorphism exerts a moderate, but statistically significant protective effect against CAD. 192,193 The effect of this polymorphism on the risk of ischemic stroke is not clear, it did not influence the risk of peripheral artery disease. 184 In young women, the Tyr204Phe polymorphism was associated with a ninefold increased risk for the occurrence of ischemic stroke.…”

Section: Factor XIIImentioning

confidence: 99%