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Isabel Tirado, Jos Manuel Soria, Jos Mateo, Artur Oliver, Juan Carlos Souto, Amparo Santamaria, Rosa Felices, Montserrat Borrell, Jordi Fontcuberta
Association after linkage analysis indicates that homozygosity for the 46CT polymorphism in the F12 gene is a genetic risk factor for venous thrombosis
In a family-based study called GAIT (Genetic Analysis of Idiopathic Thrombophilia) that included a genome-wide scan we demonstrated that a polymorphism (46CT) 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 46CT 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 46CT 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 1.515.6), suggesting that the polymorphism itself is an independent risk factor for venous thromboembolism. This study confirms that the 46CT 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.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 91, 05/2004
Pages: 899 - 904