Association of FXII 5'UTR 46C>T polymorphism with FXII activity and risk of thrombotic disease

Thrombotic diseases are caused by genetic and environmental factors. There are a number of well-characterized genetic defects that lead to increased risk of thrombosis. Results from previous studies have indicated that FXII is involved in pathogenesis of thrombophilic diseases. However, the results in this regard are highly controversial. Plasma FXII activity levels are strongly determined by a 46CγT polymorphism in the FXII gene. In the present study, the risk of thrombophilic diseases related to this polymorphism was investigated in a case-control study.

One hundred and sixty subjects were studied: 120 patients diagnosed with thrombophilia (96 venous thromboembolism, 24 arterial thrombosis), and 40 age-gender-matched controls. For each subject, FXII activity level was measured by a one-step clotting assay with FXII-deficient plasma, and 46CγT polymorphism was genotyped using a restriction fragment length polymorphism (RFLP) method.

In this study, the previous observation that individuals with different genotypes for the 46 CγT polymorphism showed significant differences in Factor XII activity levels was confirmed. Most importantly, FXII activity ≤ 68% was associated with an increased risk of venous thrombosis with an adjusted OR of 4.7 (95%CI= 1.03-21.1, P=0.04). However, it was not a risk factor for arterial thrombosis with adjusted OR of 5 (95%CI= 0.91-27.1, P=0.09). In CT and TT genotype the adjusted ORs were respectively 2 (95%CI=0.9-4.4, P=0.11) and 2.3 (95%CI=0.45-11, P=0.48) for patients with venous thrombosis compared with the controls. Similarly, the adjusted ORs in arterial thrombosis were 1.2 (95%CI=0.4-3.6, P=0.76) for CT and 1.8 (95%CI=0.2-14.9, P=0.59) for TT genotype. Thus, we did not find any association of the mutated T allele in the heterozygous or homozygous state with an increased risk of both venous and arterial thrombosis.

Lower FXII activity is not a risk factor; rather, it simply represents a risk marker for thrombosis.