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

Abstract

9 Maccarana M, Lindahl U. Mode of interaction between platelet factor 4 and heparin. The functional -4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis Deep venous thrombosis (DVT) is a common multicausal disease. The etiology of DVT includes both environmental and genetic factors [1,2]. 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. 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.Three hundred and forty six subjects with a documented episode of DVT admitted to the Division of Angiology of the Department of Internal Medicine, Medical University Graz, between December 1997 and November 1999, were enrolled as the patient group. DVT was diagnosed by ultrasonography and/or venography. A control group of similar age and sex distribution was selected from patients of the same department (n ¼ 352). Subjects were eligible as controls if they were without a history of venous (DVT, pulmonary embolism, primary varicosis) or arterial disease (coronary heart disease, cerebrovascular disease, peripheral arterial occlusive disease). The study was approved by the local ethics committee and all individuals participating in the study gave their informed consent. All subjects were Austrian and of Caucasian ethnicity.Isolation of genomic DNA and detection of prothrombin (F2 20210G>A) and factor V Leiden (F5 R506Q) genotypes were generated as described previously [12]. The F12 -4C>T polymorphism was determined by a TaqMan TM fluorogenic 5¢-nuclease assay (Applied Biosystems, Vienna, Austria) using Applera's Assays-by-Design custom service.Sequences of primers and probes were as follows: forward primer (5¢-GGATAGGCAGCTGGACCAA-3¢), reverse primer (5¢-CCAAGCTCACCAGCAGGAA-3¢), C-probe (5¢-VIC-CTCATGGCGTCCGTC-NFQ-3¢), and T-probe (5¢-FAM-CTCATGGCATCCGTC-NFQ-3¢). Statistical analysis was performed using SPSS 11.0.1 for Windows. Metric values were analyzed by Student's t-test and presented as mean ...

Major and Potential Prothrombotic Genotypes in Patients with Venous Thrombosis and in Healthy Subjects from Slovenia

“…In the present study, the frequencies of FXII -4 TT genotype in controls [12,15,35] and patients with VT [12,13,15,36] were consistent with published reports. Although no difference in FXII -4 C/T genotype distribution between all patients and controls was observed, age stratification revealed a significantly lower FXII -4 T allele frequency in patients of less than 55 years, with an OR of 0.56.…”

“…Although no difference in FXII -4 C/T genotype distribution between all patients and controls was observed, age stratification revealed a significantly lower FXII -4 T allele frequency in patients of less than 55 years, with an OR of 0.56. With few exceptions [12,37] , no prothrombotic impact of the FXII -4 T allele was observed previously [13,15,36] . On the contrary, the higher FXII -4 TT genotype frequency observed in healthy subjects could indicate a potential protective role of the FXII -4 T allele [15] .…”

“…A polymorphism recently associated with the risk of VT [12] is a cytosine to thymine substitution 4 base pairs upstream of the translation initiation ATG codon of the factor XII gene (FXII -4 C/T) [13] , originally referred to as the FXII 46 C/T polymorphism [14] . The FXII -4T allele is associated with decreased translation efficiency, leading to reduced plasma FXII levels [14] .…”

“…The FXII -4T allele is associated with decreased translation efficiency, leading to reduced plasma FXII levels [14] . Investigations on the association between FXII -4 C/T polymorphism and the risk of VT so far provided contradictory results [12,13,15] and the possible prothrombotic influence of this polymorphism remains controversial.…”

Inherited Thrombophilia and the Risk of Vascular Events

“…However, some studies failed to confirm these findings, e.g. Grunbacher et al (2005) found that F12 46-TT genotype was not associated with thrombosis risk, nor with age at first thrombosis. A metaanalysis by Johnson et al (2011) led to conclusion that evidence for association of this F12 variant with VTE was weak.…”