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Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.

ABSTRACT: BACKGROUND:Recurrent venous thromboembolism (VTE) is a common, complex disorder; however, genetic factors have been suggested to play a role in the disease development. We therefore conducted a multi-locus genetic study examining the potential associations of candidate gene variants in inflammation, thrombosis, coagulation, and lipid metabolism pathways, individually or interactively, with risk of recurrent VTE. METHODS:Using DNA samples collected at baseline in the Prevention of Recurrent Venous Thromboembolism trial (PREVENT), we genotyped 86 candidate genes polymorphisms among 43 individuals who subsequently developed recurrent VTE and among 396 individuals who remained free of recurrent event over a mean follow-up period of 2.1 years to prospectively determine whether these gene polymorphisms contribute to the risk of recurrent VTE. RESULTS:Using a single-marker 'uncorrected' analysis, CCR5 A(-2459)G [rs1799864], MMP3 5A(-1171)6A [rs3025058] and PON1 gln192arg [rs662] gene variants were associated with increased risk, and CETP C(-629)A [rs1800775] gene variant with reduced risk of recurrent VTE, respectively. Furthermore, potentially important gene-gene-interactions were detected by the Monte Carlo Markov chain Logic Regression method. CONCLUSIONS:Although the present findings are hypothesis-generating and require confirmation in an independent investigation, our study provides a practical example of detecting epistasis in common, complex diseases.

SUBMITTER: Zee RY

PROVIDER: S-EPMC2693946 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.

Zee Robert Y L RY Bubes Vadim V Shrivastava Sanjay S Ridker Paul M PM Glynn Robert J RJ

Clinica chimica acta; international journal of clinical chemistry 20090401 1-2

<h4>Background</h4>Recurrent venous thromboembolism (VTE) is a common, complex disorder; however, genetic factors have been suggested to play a role in the disease development. We therefore conducted a multi-locus genetic study examining the potential associations of candidate gene variants in inflammation, thrombosis, coagulation, and lipid metabolism pathways, individually or interactively, with risk of recurrent VTE.<h4>Methods</h4>Using DNA samples collected at baseline in the Prevention of ...[more]

PMID: 19263529

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Project description:ImportanceThe size of the risk of recurrent venous thromboembolism (VTE) after surgery in patients with a history of VTE is not well known.ObjectivesTo estimate the risk of and to identify the factors associated with recurrent VTE in patients undergoing surgery who have a history of VTE.Design, setting, and participantsThis population-based, follow-up cohort study includes patients with VTE who participated in the Multiple Environment and Genetic Assessment (MEGA) study. Original data were collected from March 1999 to April 2010. Data analysis began in June 1999 and ended in April 2010.ExposuresSurgery following a first VTE.Main outcomes and measurementsKaplan-Meier analyses were used to estimate cumulative incidences of recurrent VTE. Cox regression with a time-dependent covariate (surgery) was used to calculate the hazard ratio (HR) for developing recurrent VTE after surgery compared with no surgery.ResultsOverall, 3741 patients (mean [SD] age, 48.4 [12.8] years; 2020 [54.0%] women) with a history of VTE were included in the analysis, amounting to 18 899 person-years, with a median (interquartile range) follow-up of 5.7 (3.0-7.2) years. Of the 3741 patients, 580 (15.5%) underwent surgery and 601 (16.1%) developed a recurrent thrombotic event. The 1-month cumulative incidence of recurrent VTE for all surgery types was 2.1% (95% CI, 1.2%-3.6%), which increased to 3.3% (95% CI, 2.1%-5.1%) at 3 months and 4.6% (95% CI, 3.1%-6.6%) at 6 months. At 6 months, risk of recurrent VTE ranged from 2.3% to 9.3%, depending on surgery type. In addition to surgery type, factor V Leiden mutation (HR, 3.4; 95% CI, 1.6-7.4) and male sex (HR, 2.7; 95% CI, 1.3-5.8) were associated with increased risk of recurrent VTE.Conclusions and relevanceSurgery was associated with an increased risk of recurrent VTE in patients with a history of VTE; risk remained high for up to 6 months after the procedure. This study suggests that high-risk individuals may be identified based on surgery type, sex, and the presence of factor V Leiden mutation. These findings stress the need for revision of the current thromboprophylactic approach to prevent recurrence in these patients.

Project description:ImportanceIt is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE).ObjectiveTo estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism.Design, setting, and participantsThis study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018.ExposuresA panel of several established cardiovascular risk factors.Main outcomes and measuresHazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI).ResultsOf the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers.Conclusions and relevanceOlder age, smoking, and adiposity were consistently associated with higher VTE risk.

Dataset Information

Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.

Publications

Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.

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