The 46C→T polymorphism in the factor XII gene (F12) and the risk of venous thrombosis

Abstract

The 46CfiT polymorphism in the factor XII gene (F12) and the risk of venous thrombosis The precise role of factor XII (FXII) in the regulation of blood coagulation and fibrinolysis is still undefined. Activation of FXII initiates both the kinin-forming cascade and the intrinsic coagulation and fibrinolytic pathways. Subjects with severe FXII deficiency show a prolonged activated partial thromboplastin time but do not have a bleeding tendency, which suggests a minor role for FXII in the regulation of fibrin formation in vivo. The observation that FXII is also involved in the activation of the fibrinolytic system led to the hypothesis that partial or severe FXII deficiency might result in impaired fibrinolysis and as a consequence in a thrombotic tendency. Indeed, a high frequency (9-15%) of reduced plasma FXII levels was found among patients with (venous) thrombosis [1,2] and women with recurrent miscarriages [3], a condition often associated with a thrombophilic state. However, Koster et al. R . M . B E R T I N A , * S . R . P O O R T , * H . L . V O S * and F . R . R O S E N D

The functional -4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis

“…Coagulation factor XII (FXII, Hagemann factor) plays a central role in the initiation of coagulation and fibrinolysis, but its physiological role is still under discussion. Some studies reported a correlation between FXII levels and the prevalence of venous thrombosis [3,4] but others did not find reduced FXII levels among thrombosis patients [5,6].A common C>T polymorphism four nucleotides upstream of the start codon of the FXII gene (F12 -4C>T, NCBI SNP ID rs17876008) has been associated with lower FXII levels [7][8][9][10]. This polymorphism has previously been described as 46C>T based upon the numbering from the beginning of the transcription, but this notation does not conform to recommendations for human gene mutation nomenclature [11] and will not be used in this study.…”

“…Coagulation factor XII (FXII, Hagemann factor) plays a central role in the initiation of coagulation and fibrinolysis, but its physiological role is still under discussion. Some studies reported a correlation between FXII levels and the prevalence of venous thrombosis [3,4] but others did not find reduced FXII levels among thrombosis patients [5,6].…”

“…The T variant lacks a Kozak consensus sequence, resulting in a decreased translational efficiency and lower FXII plasma levels [7]. Tirado et al [8] suggested the -4 C>T polymorphism as a genetic risk factor for DVT, but a larger subsequent study failed to find an association between that polymorphism and DVT [6]. The aim of our study was therefore to investigate the potential association of this polymorphism with DVT.…”

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

“…4). This SNP represents a common T/C polymorphism with prevalence of the T allele estimated at 20% in Caucasian and 70% in Asian populations (27)(28)(29)(30)(31). Kanaji and colleagues demonstrated that the T allele reduces protein levels, and proposed that the mechanism could be due to disruption of the Kozak consensus sequence or to the introduction of a uORF, although these hypotheses were not tested (30).…”

Aetiology of Venous Thrombosis

“…Elevated fibrinogen (hyperfibrinogenaemia) was found to promote faster fibrin formation and increased thrombus fibrin content, density, strength and stability. Hyperfibrinogenaemia was also found to have increased thrombolysis resistance, which explains more the association with VTE (Koster et al, 1995a;Poort et al, 1996;O'Donnell et al, 1997;Meijers et al, 2000;Kamphuisen et al, 2001;de Visser et al, 2001;Bertina et al, 2005;Machlus et al, 2011).…”