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Discovering novel risk factors for venous thrombosis: a candidate-gene approach.

ABSTRACT: The candidate-gene approach can be used to locate and identify genetic variations that are associated with a particular phenotype. This gene-centric approach assumes that there exists important genetic variation within genes that can influence health. Identifying known genes which are candidates for the phenotype of interest can be accomplished using existing knowledge about biology or using findings from genome-wide association studies. Genetic variation can be characterized locally by single nucleotide polymorphisms (SNPs) or insertion-deletions, or it can be characterized more broadly in terms of haplotypes and diplotypes, which usually need to be inferred statistically. As an example, we present a candidate-gene approach to identify novel associations between variation in 24 clotting genes and the risk of incident venous thrombosis.

SUBMITTER: Smith NL

PROVIDER: S-EPMC2987733 | biostudies-other | 2009

REPOSITORIES: biostudies-other

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Discovering novel risk factors for venous thrombosis: a candidate-gene approach.

Smith Nicholas L NL Rice Kenneth M KM Lumley Thomas T Heckbert Susan R SR Psaty Bruce M BM

Thrombosis research 20090101

The candidate-gene approach can be used to locate and identify genetic variations that are associated with a particular phenotype. This gene-centric approach assumes that there exists important genetic variation within genes that can influence health. Identifying known genes which are candidates for the phenotype of interest can be accomplished using existing knowledge about biology or using findings from genome-wide association studies. Genetic variation can be characterized locally by single n ...[more]

PMID: 19303500

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Project description:Background and purposeCerebral venous thrombosis (CVT) is a special cerebrovascular disease that accounts for around 0.5%-1.0% of all strokes and often occurs in younger adults. Intracranial hypertension is the most frequent symptom of acute CVT due to venous occlusion. This study aimed to ascertain the risk factors for intracranial hypertension after CVT and to investigate whether intracranial hypertension at diagnosis may affect patient outcomes.MethodsWe performed a retrospective cohort analysis of all patients treated for acute/subacute CVT at our department between 2018 and 2021. Logistic regression analysis was performed to identify potential risk factors associated with intracranial hypertension after CVT and clinical outcomes at the 6-month follow-up.ResultsA total of 293 acute/subacute CVT survivors were eligible for inclusion, with 245 patients (83.60%) experiencing concomitant intracranial hypertension at diagnosis. In the multivariable regression analysis, hereditary thrombophilia (OR 2.210, 95% CI 1.148-4.254, p = 0.018) and thrombosis location of superior sagittal sinus (SSS) and right lateral sinus (LS) (OR 4.115, 95% CI 1.880-9.010, p = 0.000) were independently associated with intracranial hypertension. 83.67% of patients with intracranial hypertension after CVT had favorable functional outcomes (mRS score, 0-2), whereas they more often had residual visual impairment (15.51% vs. 4.17%, p = 0.036) at follow-up. The risk factors for residual visual impairment were papilledema (OR 2.971, 95% CI 1.231-7.170, p = 0.015) and visual disturbances at diagnosis (OR 2.869, 95% CI 1.123-7.327, p = 0.028), thrombosis location (SSS and right LS [OR 10.811, 95% CI 4.208-27.773, p = 0.000]; SSS and left LS [OR 3.139, 95% CI 1.409-6.995, p = 0.005]), and CVT recurrence (OR 4.763, 95% CI 1.556-14.584, p = 0.006).ConclusionsIntracranial hypertension is the most common clinical symptom of acute CVT. At follow-up, patients with intracranial hypertension after CVT were more prone to develop residual visual impairment.

Project description:BACKGROUND: Previously, we demonstrated that hypofibrinolysis, a decreased capacity to dissolve a blood clot as measured with an overall clot lysis assay, increases the risk of venous thrombosis. Here, we investigated the combined effect of hypofibrinolysis with established risk factors associated with hypercoagulability. METHODS AND FINDINGS: Fibrinolytic potential was determined with a plasma-based clot lysis assay in 2,090 patients with venous thrombosis and 2,564 control participants between 18 and 70 y of age enrolled in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based case-control study on venous thrombosis. Participants completed a standardized questionnaire on acquired risk factors. Hypofibrinolysis alone, i.e., clot lysis time (CLT) in the fourth quartile (longest CLT) (in absence of the other risk factor of interest) increased thrombosis risk about 2-fold relative to individuals with CLT in the first quartile (shortest CLT). Oral contraceptive use in women with CLT in the first quartile gave an odds ratio (OR) of 2.6 (95% confidence interval [CI] 1.6 to 4.0), while women with hypofibrinolysis who used oral contraceptives had an over 20-fold increased risk of venous thrombosis (OR 21.8, 95% CI 10.2 to 46.7). For immobilization alone the OR was 4.3 (95% CI 3.2 to 5.8) and immobilization with hypofibrinolysis increased the risk 10.3-fold (95% CI 7.7 to 13.8). Factor V Leiden alone increased the risk 3.5-fold (95% CI 2.3 to 5.5), and hypofibrinolysis in factor V Leiden carriers gave an OR of 8.1 (95% CI 5.3 to 12.3). The combination of hypofibrinolysis and the prothrombin 20210A mutation did not synergistically increase the risk. All ORs and 95% CIs presented are relative to individuals with CLT in the first quartile and without the other risk factor of interest. CONCLUSIONS: The combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.

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Discovering novel risk factors for venous thrombosis: a candidate-gene approach.

Publications

Discovering novel risk factors for venous thrombosis: a candidate-gene approach.

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