Genetic variants associated with deep vein thrombosis: the F11 locus

Abstract

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.

KNG1 Ile581Thr and susceptibility to venous thrombosis

“…The association of F11 SNPs with VT risk is not new because 2 F11 SNPs, rs2036914 and rs2289252, were previously found to be associated with VT in the Leiden Thrombophilia study. 19 None of these 2 SNPs was available in our GWAS dataset, nor were they in strong linkage disequilibrium with any of the F11 SNPs associated with VT in the present work (supplemental Table 5). In-depth haplotype analysis would be further required to disentangle the exact contribution of F11 SNPs to VT risk and aPTT variability, but this research is out of the scope of the present report.…”

Multiple SNP testing improves risk prediction of first venous thrombosis

“…Nine SNPs were added from a large SNP association analysis, including subsequent fine mapping that we performed recently in LETS and MEGA. 15,16 Another added SNP was recently identified in a follow-up study of a genome-wide association study and replicated in the FARIVE study and the MEGA study. 17 Among the 40 SNPs in the initial selection, we studied linkage disequilibrium and mutually adjusted SNPs within genes.…”

“…Table 1 lists all associations between SNPs and venous thrombosis in the MEGA population and the average estimated effect size in the literature. [13][14][15][16][17][19][20][21][22][23][24][25][26] Not all SNPs were associated with venous thrombosis in our study populations; nevertheless, we included all 31 SNPs in the genetic risk score because these SNPs had been associated with venous thrombosis in other studies.…”

Inherited Thrombophilia and the Risk of Vascular Events

“…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. The effect of CYP4V2 and GP6 loci polymorphisms (SNPs rs1613662 and rs13146272) was further confirmed by Tregouet et al (2009), and the effect of F11 polymorphisms (SNPs rs2289252 and rs2036914) by Li et al (2009). Recently, in a multi-stage multi-design study, Antoni et al (2010) found evidence that BAI3 locus (encoding brain specific angiogenesis inhibitor 3) is associated with early-onset VTE; rs9363864-AA genotype was associated with a lower risk for VTE and low levels of FVIII and VWF.…”