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C-B4-02: Determining Genetic Risk Factors for Post- Hospitalization development of Deep-Vein Thrombosis

ABSTRACT: Background: Venothromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) are significant health care problems. A highly specific DVT risk stratification model requires a combination of genetic, environmental, clinical, laboratory and radiographic measurements. Genetic factors associated with DVT in post-hospitalized medical and surgical patients are incompletely understood. Aim: Using the Personalized Medicine Research Project (PMRP) population and a limited number of disease associated polymorphisms were used to determine whether these markers were associated with DVT in the post-hospitlalization period. Methods: Marshfield Clinic patients who have experienced a DVT between 1999 and 2007 enrolled in the PMRP were genotyped for 52 disease associated polymorphisms (N=1124). From these individuals we identified 451 who experienced a DVT after post-hospitalization for a medical (N=164) or surgical (N=136) procedure or both (N=151). This cohort was compared to the PMRP population that had a recorded hospitalization without a post-hospitalization DVT during the same time period (N=1662). Results: Polymorphisms in APOB (rs1042031), PLAU (rs2227564), HTR2A (rs6313) and the Vitamin D receptor haplotype (rs731236 and rs7975232) were associated with post hospitalization DVT. When the population that incurred a DVT was stratified by DVT category (post medical, post surgical or both), the PLAU polymorphism was most strongly associated with individuals experiencing a DVT post-surgically. Vitamin D receptor haplotype was significantly associated with individuals experiencing both post medical and post surgical DVTs, and polymorphisms associated with cholesterol and lipid levels were most likely to be associated with post-medical DVTs. Conclusions: This hypothesis generating study demonstrates that there are many polymorphisms that are associated with DVT that have yet to be characterized. Categorization of associated DVT polymorphisms will involve careful interrogation of both the environmental conditions as well as genetic alleles of individuals. Genes such as PLAU, HTR2A, and Vitamin D are just now being investigated for thrombogenic effects and in future may lead to a better understanding of indentifying the individuals at risk for a DVT post hospitilization.

SUBMITTER: Cross D

PROVIDER: S-EPMC3006593 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Project description:Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. SUMMARY: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10-1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11, and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies.

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C-B4-02: Determining Genetic Risk Factors for Post- Hospitalization development of Deep-Vein Thrombosis

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