Association after linkage analysis indicates that homozygosity for the 46C→T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis

Abstract

In a family-based study called GAIT (Genetic Analysis of Idiopathic Thrombophilia) that included a genome-wide scan we demonstrated that a polymorphism (46C-->T) in the F12 locus jointly influences variability of plasma (Factor XII) FXII levels and susceptibility to thrombotic disease. It then became germane to determine the prevalence of the 46C-->T polymorphism and its relative risk of thrombotic disease. We followed up evidence for genetic linkage with a case-control study, including 250 unrelated consecutive Spanish patients suffering from venous thrombotic disease and 250 Spanish subjects matched for sex and age as a controls. We measured FXII levels and genotyped the 46C-->T polymorphism, as well as a number of classical risk factors for thrombotic disease. We confirmed that individuals with different genotypes for this polymorphism showed significant differences in their FXII levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of thrombosis (adjusted OR of 4.82; 95% CI 1.5-15.6), suggesting that the polymorphism itself is an independent risk factor for venous thromboembolism. This study confirms that the 46C-->T polymorphism is a genetic risk factor for venous thrombosis in the Spanish population. In addition, our results confirm that a genome-wide scan coupled with a classical case-control association study is an extremely valuable approach to identify DNA variants that affect complex diseases.

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

“…Similar results were obtained for men and women, and for subjects > 45 years and £ 45 years. Our results confirm the findings of Franco et al [13] and differ from those reported by Tirado et al [12] In fact, the OR of 0.82 that we observed for 46TT carriers is identical to the one reported by Franco et al…”

“…A previously reported polymorphism in the 5¢-untranslated region of the F12 gene (46 CfiT) [10], of which the T-allele is associated with reduced plasma FXII levels [10,11], explained part of the linkage signal [9]. In a subsequent study Tirado et al reported a 3-fold increased risk of venous thrombosis for carriers of the 46TT genotype (crude OR 3.1; 95% CI 1.1-8.7) and concluded that the 46T-allele is an independent genetic risk factor for venous thrombosis in the Spanish population [12]. A previous study from Franco et al reported that homozygous 46T carriers did not have an increased risk of venous thrombosis (OR 0.8, 95% CI 0.3-1.9) [13].…”

Inherited Thrombophilia and the Risk of Vascular Events

“…Common F12 variant has attracted much research interest, but the results were not unequivocal. F12 C-46T variant (rs1801020) was reported to be associated with increased VTE risk (homozygous carriers of T allele compared to noncarriers; Tirado et al, 2004). This association was also observed in a number of other studies, e.g.…”

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).…”