HE INCIDENCE OF DEEP VEIN thrombosis (DVT) is 1 per 1000 person-years. 1 The10-yearrecurrence risk is 30%. 2 Deep vein thrombosis can lead to life-threatening pulmonary embolism. 3 Deep vein thrombosis is caused by acquired and genetic risk factors. Acquired risk factors include age, hospitalization, cancer, pregnancy, hormone therapy, and surgery. 2 Family and twin studies indicate that genetics ac-countsforabout60%oftheriskforDVT. 4,5 Deficiencies of natural anticoagulants antithrombin, protein C, and protein S are strong risk factors for DVT; however, the variantscausingthesedeficienciesarerare and explain only about 1% of all DVTs. 6 Two more common genetic variants, Factor V Leiden (FVL) and prothrombin G20210A, have been consistently found to be associated with DVT 7,8 but still only explain a fraction of the DVT events. 6 It has been suggested that 2 or more risk factors are needed for thrombosis. 6,9,10 The identification of additional common gene variants associated with DVT will improve the ability to predict risk for DVT and increase understanding of this disease. Therefore, we investigated whether any of 19 682 primarily missense single-nucleotide polymorphisms (SNPs) were associated with DVT in 3 large case-control studies. METHODS Study Populations and Data Collection The 3 studies (LETS, MEGA-1 and MEGA-2) in the present analysis are derived from 2 large population-based case-control studies: the Leiden Throm-bophilia Study (LETS) 11 and the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA study). 12 These

Background: A positive family history of venous thrombosis may reflect the presence of genetic risk factors. Once a risk factor has been identified, it is not known whether family history is of additional value in predicting an individual's risk. We studied the contribution of family history to the risk of venous thrombosis in relation to known risk factors.

There are no risk models available yet that accurately predict a person's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosisassociated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study,

To cite this article: Li Y, Bezemer ID, Rowland CM, Tong CH, Arellano AR, Catanese JJ, Devlin JJ, Reitsma PH, Bare LA, Rosendaal FR. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost 2009; 7: 1802-8. Summary. Background: Recent studies have found associations between deep vein thrombosis (DVT) and single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that contains genes encoding factor XI (F11), a cytochrome P450 family member (CYP4V2), and prekallikrein (KLKB1). Objective: We investigated which of the common SNPs in this locus are independently associated with DVT. Methods: The study populations were the Leiden Thrombophilia Study (LETS) (443 DVT cases and 453 controls) and the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study) (2712 DVT cases and 4634 controls). We assessed the association between DVT and 103 SNPs in a 200 kb region using logistic regression. Results: We found that two SNPs (rs2289252 and rs2036914 in F11) were independently associated with DVT. After adjusting for age, sex, and the other SNP, the odds ratios (risk vs. non-risk homozygotes) of these two SNPs were 1.49 for rs2289252 (95% CI, 1.25-1.76) and 1.33 for rs2036914 (95% CI, 1.11-1.59). We found that rs2289252 was also associated with FXI levels, as has been previously reported for rs2036914; these two SNPs remained associated with DVT with somewhat attenuated risk estimates after adjustment for FXI levels. Conclusion: Two SNPs, rs2289252 and rs2036914 in F11, appear to independently contribute to the risk of DVT, a contribution that is explained at least in part by an association with FXI levels.

This study supports the hypothesis of an influence of alcohol intake on sex hormone concentrations in blood.