F9 Malmö, factor IX and deep vein thrombosis

Abstract

Background: We recently reported the association between the Malmö sequence variant in F9 (rs6048) and deep vein thrombosis.

Design and methods: We 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.

Results: In 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 single-nucleotide 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.

Conclusions: The 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.

Figure 1.

Combined analysis of F9 Malmö with deep vein thrombosis in men and women.

Figure 2.

In the selected region on the X chromosome (positions 138,404,951 to 138,494,063), 48 SNPs with MAF>0.02 were genotyped in the HapMap CEPH population. The figure represents pairwise linkage disequilibrium (r²) between the 48 SNPs. High r² values are represented as black squares, fading to gray and white as linkage disequilibrium becomes weaker. Based on these r² values, 18 tag SNPs were selected of which 15 were genotyped in LETS (black triangles). In addition, we selected 14 candidate SNPs (gray triangles), of which one (rs2235708) was located outside the selected region. The arrow indicates F9 Malmö (rs6048).