Gene Variants Associated With Deep Vein Thrombosis

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 03/2008; 299(11):1306-14. DOI: 10.1001/jama.299.11.1306
Source: PubMed


The genetic causes of deep vein thrombosis (DVT) are not fully understood.
To identify single-nucleotide polymorphisms (SNPs) associated with DVT.
We used 3 case-control studies of first DVT. A total of 19 682 gene-centric SNPs were genotyped in 443 cases and 453 controls from the Leiden Thrombophilia Study (LETS, 1988-1992). Twelve hundred six SNPs associated with DVT were reinvestigated in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study (MEGA-1, 1999-2004) in a subset of 1398 cases and 1757 controls. Nine SNPs associated with DVT in both LETS and MEGA-1 were investigated a third time in 1314 cases and 2877 controls from MEGA-2, a second subset of MEGA. Additional SNPs close to one SNP in CYP4V2 were genotyped in LETS and MEGA-1.
Odds ratios (ORs) for DVT were estimated by logistic regression. False discovery rates served to investigate the effect of multiple hypothesis testing.
Of 9 SNPs genotyped in MEGA-2, 3 were strongly associated with DVT (P < .05; false discovery rate < or =.10): rs13146272 in CYP4V2 (risk allele frequency, 0.64), rs2227589 in SERPINC1 (risk allele frequency, 0.10), and rs1613662 in GP6 (risk allele frequency, 0.84). The OR for DVT per risk allele was 1.24 (95% confidence interval [95%CI], 1.11-1.37) for rs13146272, 1.29 (95% CI, 1.10-1.49) for rs2227589, and 1.15 (95% CI, 1.01-1.30) for rs1613662. In the region of CYP4V2, we identified 4 additional SNPs (in CYP4V2, KLKB1, and F11) that were also associated with both DVT (highest OR per risk allele, 1.39; 95% CI, 1.11-1.74) and coagulation factor XI level (highest increase per risk allele, 8%; 95% CI, 5%-11%).
We identified SNPs in several genes that were associated with DVT. We also found SNPs in the region around the SNP in CYP4V2 (rs13146272) that were associated with both DVT and factor XI levels. These results show that common genetic variation plays an important role in determining thrombotic risk.

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Available from: Carine J M Doggen,
    • "It occurs in approximately 1 per 1000 persons per year, with a case-fatality rate up to 25% at 1 year [1]. Several acquired and genetic risk factors for VTE have been identified so far [2] [3], but the causes of VTE remain unexplained in approximately 40% of cases [4]. "
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    ABSTRACT: An association between high red cell distribution width (RDW) and venous thromboembolism (VTE) has been observed. However, it is not known whether this association differs within various manifestations of VTE, nor if there is an interaction between RDW and thrombophilia abnormalities on the risk of VTE. To investigate whether RDW is a marker of the risk of VTE; to identify subgroups of patients in which the association between RDW and VTE is stronger; to investigate a possible interaction between RDW and thrombophilia abnormalities. Case-control study on 730 patients with a first objectively-confirmed VTE episode (300 unprovoked and 430 provoked) consecutively referred to our Center between 2007 and 2013, and 352 healthy controls. Blood was taken for a thrombophilia work-up and a complete blood count, including RDW, at least three months after VTE. Individuals with RDW above the 90(th) percentile (>14.6%) had a 2.5-fold increased risk of VTE compared to those with RDW ≤90(th) percentile, independently of age, sex, body mass index, other hematological variables and renal function (adjusted odds ratio: 2.52 [95%CI:1.42-4.47]). The risk was similar for unprovoked and provoked VTE, and slightly higher in patients with pulmonary embolism (adjusted odds ratio 3.19 [95%CI:1.68-6.09]) than in those with deep vein thrombosis alone (2.29 [95%CI:1.22-4.30]). No interaction between high RDW and thrombophilia abnormalities on the risk of VTE was observed. Our findings confirm RDW as an independent and easily available marker for stratification of the risk of VTE. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Thrombosis Research 07/2015; 136(3). DOI:10.1016/j.thromres.2015.07.020 · 2.45 Impact Factor
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    • "This variant is located within the intronic region of F11, and is not known to be functional. Other studies have also reported associations between SNPs in F11 and VT [18,19,30-32]. In these studies, the strongest associations were shown for the minor allele of rs2289252 and rs3756008, and the major allele of rs2036914, with an increased risk of VT. "
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    ABSTRACT: Coagulation factor XI (FXI) has an important role in the propagation and stabilization of a thrombus upon vessel injury. High FXI levels have been implicated in thrombotic diseases including ischemic stroke. The aim of our study was to investigate whether FXI gene (F11) variants are associated with ischemic stroke. The discovery sample, the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), included 844 patients with ischemic stroke and 668 controls, all aged 18-70 years. Replication was performed in the Lund Stroke Register (LSR) and Malmö Diet and Cancer study (MDC), together including 1213 patients and 788 controls up to 70 years of age, and in total 3145 patients and 1793 controls (18-102 years). Seven F11 single-nucleotide polymorphisms (SNPs) were selected using a tagging approach. The SNPs rs3733403, rs925451, and rs1593 showed independent associations with overall ischemic stroke in SAHLSIS, ORs of 0.74 (95% CI 0.59-0.94), 1.24 (95% CI 1.06-1.46), and 0.70 (95% CI 0.55-0.90), respectively. The association for rs925451 was replicated in the LSR and MDC sample in a pre-specified analysis of subjects aged 70 years or younger, OR of 1.16 (95% CI 1.00-1.34), whereas no SNP was replicated when all ages were included. In line with this, one F11 haplotype was associated with overall ischemic stroke in the discovery sample and in the replication sample ≤70 years. We found significant associations between F11 variation and overall ischemic stroke up to 70 years of age. These findings motivate further studies on the role of F11 in ischemic stroke, especially in younger individuals.
    PLoS ONE 09/2013; 8(9):e75286. DOI:10.1371/journal.pone.0075286 · 3.23 Impact Factor
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    • "Blood coagulation serine protease factor XI (FXI) contributes to hemostasis by activating coagulation factor IX [1]. Although bleeding associated with FXI deficiency is relatively mild, there has been a resurgence of interest in FXI, because candidate gene studies revealed a role of high FXI levels as a risk factor for venous thrombosis [2,3]. Factor XI, like the blood coagulation protease factors II, VII, IX, X, XII and XIIIb, is produced primarily in hepatocytes. "
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that harbors the coagulation factor XI (F11), prekallikrein (KLKB1), and a cytochrome P450 family member (CYP4V2) genes are associated with deep venous thrombosis (DVT). These SNPs exert their effect on DVT by modifying the circulating levels of FXI. However, SNPs associated with DVT were not necessarily all in F11, but also in KLKB1 and CYP4V2. Here, we searched for evidence for common regulatory elements within the 4q35.2 locus, outside the F11 gene, that might control FXI plasma levels and/or DVT risk. To this end, we investigated the regulation of the orthologous mouse gene cluster under several metabolic conditions that impact mouse hepatic F11 transcription. In livers of mice in which HNF4α, a key transcription factor controlling F11, was ablated, or reduced by siRNA, a strong decrease in hepatic F11 transcript levels was observed that correlated with Cyp4v3 (mouse orthologue of CYP4V2), but not by Klkb1 levels. Estrogens induced hepatic F11 and Cyp4v3, but not Klkb1 transcript levels, whereas thyroid hormone strongly induced hepatic F11 transcript levels, and reduced Cyp4v3, leaving Klkb1 levels unaffected. Mice fed a high-fat diet also had elevated F11 transcription, markedly paralleled by an induction of Klkb1 and Cyp4v3 expression. We conclude that within the mouse F11, Klkb1, Cyp4v3 gene cluster, F11 and Cyp4v3 frequently display striking parallel transcriptional responses suggesting the presence of shared regulatory elements.
    PLoS ONE 09/2013; 8(9):e74637. DOI:10.1371/journal.pone.0074637 · 3.23 Impact Factor
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