F9 Malmo, factor IX and deep vein thrombosis

Abstract

BackgroundWe recently reported the association between the Malmö sequence variant in F9 (rs6048) and deep vein thrombosis. Design and MethodsWe aimed to study whether the association between F9 Malmö and deep vein thrombosis is explained by linkage disequilibrium with nearby single-nucleotide polymorphisms, and whether the association is explained biologically by F9 Malmö affecting factor IX antigen levels or activation of factor IX. We investigated the association of F9 Malmö and 28 nearby single-nucleotide polymorphisms with deep vein thrombosis in men from two case-control studies, LETS (n=380) and MEGA (n=1,469). We assessed the association of F9 Malmö with factor IX antigen level in male control subjects from LETS (n=191) and two subsets of MEGA (n=823 and n=484) and the association with endogenous thrombin potential in LETS control men. We studied the association between F9 Malmö and factor IX activation peptide in 1,199 healthy middle-aged men from the NPHS-II cohort. ResultsIn the combined LETS and MEGA studies, the odds ratio (95% confidence interval) for the G allele of F9 Malmö, compared with the A allele, was 0.80 (0.69-0.93). One singlenucleotide polymorphism in F9, rs422187, was strongly linked to F9 Malmö (r 2 =0.94) and was similarly associated with deep vein thrombosis. No other single-nucleotide polymorphism or haplotype tested was more strongly associated. Factor IX antigen level, factor IX activation peptide levels and endogenous thrombin potential did not differ between F9 Malmö genotypes. ConclusionsThe F9 Malmö sequence variant was the most strongly associated with deep vein thrombosis among common single-nucleotide polymorphisms in the region. However, the biological mechanism by which F9 Malmö affects risk remains unknown.Key words: factor IX, single nucleotide polymorphism, venous thrombosis.Citation: Bezemer ID, Arellano AR, Tong C, Rowland CM, Ireland HA, Bauer KA, Catanese J, Reitsma PH, Doggen CJM, Devlin JJ, Rosendaal FR, and Bare LA. F9 Malmö, factor IX and deep vein thrombosis. Haematologica 2009; 94:693-699. doi:10.3324/haematol.2008

High coagulant factors & venous thrombosis

“…4 So far, the effects of coagulant factors IX through XIII have been investigated in only a few case-control studies, including the Leiden Thrombophilia Study (LETS) 5 and, more recently, the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study. 6,7 Prospective cohort studies have been lacking so far. 5 In this issue of Blood, an efficient nested case-control design has been used within LITE, a prospective cohort study in individuals aged 45 to 100 years, with a median follow-up period of more than 9 years.…”

Inherited Thrombophilia and the Risk of Vascular Events

“…Buil et al (2010) reported that a new locus, C4BPB/C4BPA (coding for C4-binding protein), is involved in susceptibility to VT through a still unknown, but protein S-independent mechanism. Bezemer et al (2008) found SNPs significantly associated with VT in CYP4V2/KLKB1/F11 gene cluster, as well as in the GP6 and SERPINC1 genes. Three SNPs were strongly associated with VT: rs13146272 in CYP4V2, rs2227589 in SERPINC1 and rs1613662 in GP6; 4 additional SNPs (in CYP4V2, KLKB1, and F11) were also associated with VT.…”

Factor IX and deep vein thrombosis

“…In contrast, functional genotypes for α-or γ-fibrinogen were not associated with fibrinogen levels, but were associated with risk of stroke; possibly because they affect not fibrinogen levels, but rather fibrin structure. Together with the report of Bezemer et al, 11 this study suggests that genetic epidemiological studies need to progress from simply assay of levels of intermediate phenotypes (e.g. coagulation factors) to inclusion of assay functions.…”

“…Second, identification of functional genotypes which alter either factor IX levels, or factor IX function and epidemiological studies of their associations with risk of venous or arterial thrombosis: Mendelian randomization studies. 10 In this edition of Haematologica, Bezemer and colleagues 11 report a study of the Mendelian randomization approach. In a previous study of almost 20,000 potentially functional single-nucleotide polymorphisms (SNPs) for association with deep vein thrombosis (DVT), they identified an A>G sequence variant in the gene encoding factor IX (rs 6048, F9 Malmö).…”

“…First, further epidemiological studies should be performed on functional phenotypes (factor IX activity, antigen, activation peptides, and related activities such as thrombin generation in vitro) and risk of both venous and arterial thrombosis. Second, such studies should include potential genotypes of interest: the report of Bezemer et al 11 establishes a case for both factor IX Malmö and the rs 422187 mutation in such studies.…”