F9 Malmo, factor IX and deep vein thrombosis

Background We recently reported the association between the Malmo sequence variant in F9 (rs6048) and deep vein thrombosis. Design and Methods We aimed to study whether the issociation between F9 Malmo and deep vein thrombosis is explained by linkage disequilibrium with nearby single-nucleotide polymorphisms, and whether the association is explained biologically by F9 Malmo affecting factor IX antigen levels or activation of factor IX. We investigated the association of F9 Malmo 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 Malmo 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 Malmo and factor IX activation peptide in 1,199 healthy middle-aged men from the NPHS-II cohort. Results In the combined LETS and MEGA studies, the odds ratio (95% confidence interval) for the G allele of F9 Malmo, compared with the A allele, was 0.80 (0.69-0.93). One single-nucleotide polymorphism in F9, rs422187, was strongly linked to F9 Malmo (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 Malmo genotypes. Conclusions The F9 Malmo 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 Malmo affects risk remains unknown.