title: 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.
authors.affiliation: Unitat d'Hemostasi i Trombosi, Departament d'Hematologia, Hospital de la Santa Creu i Sant Pau, C/ Sant Antoni Ma Claret, 167. 08025, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Tirado
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Soria
authors.forename: José
authors.initials: J
authors.lastname: Mateo
authors.forename: Artur
authors.initials: A
authors.lastname: Oliver
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.forename: Amparo
authors.initials: A
authors.lastname: Santamaria
authors.forename: Rosa
authors.initials: R
authors.lastname: Felices
authors.forename: Montserrat
authors.initials: M
authors.lastname: Borrell
authors.forename: Jordi
authors.initials: J
authors.lastname: Fontcuberta
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005174:Factor XII / Q000032:analysis / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D013030:Spain / Q000453:epidemiology; D020246:Venous Thrombosis / Q000235:genetics*
chemical_list: D005174:Factor XII