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Integrin beta-3 genetic variants and risk of venous thromboembolism in colorectal cancer patients.

ABSTRACT: BACKGROUND:Integrin ?3 is involved in tumor and endothelial cell biology as well as in platelet aggregation. Herein, we evaluated the predictive potential of three germline single nucleotide polymorphisms (SNPs) in the integrin ?3 gene (rs3809865, rs5918 and rs4642) to predict the risk of venous thromboembolism (VTE) in colorectal cancer (CRC) patients, which is one of the leading causes of death among cancer patients. METHODS:112 patients diagnosed with CRC enrolled in the prospective Vienna Cancer and Thrombosis Study (CATS) were assessed with a median follow-up of 46 months. DNA was isolated from venous blood samples and SNPs were analyzed by the PCR-RFLP method. RESULTS:VTE occurred in 12% (n=13) of all patients. The SNPs rs5918 and rs4642 were not associated with VTE risk. For rs3809565, 23% (n=11) of patients had the A/A genotype, 4% (n=2) had the A/T genotype, but none (0%) had the T/T genotype. In the univariate analysis, patients with the A/A genotype had a significantly higher risk to develop VTE compared to the other polymorphisms (P=0.0005 after Fine and Gray). In the multivariable analysis, the predictive value remained significant. CONCLUSIONS:This study identified the rs3809865 A/A genotype as an independent risk factor for VTE in CRC patients. Our findings would help identify high risk patients and would be essential for tailored anticoagulant prophylaxis.

SUBMITTER: Bianconi D

PROVIDER: S-EPMC7496222 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Integrin beta-3 genetic variants and risk of venous thromboembolism in colorectal cancer patients.

Bianconi Daniela D Schuler Alexandra A Pausz Clemens C Geroldinger Angelika A Kaider Alexandra A Lenz Heinz-Josef HJ Kornek Gabriela G Scheithauer Werner W Zielinski Christoph C CC Pabinger Ingrid I Ay Cihan C Prager Gerald W GW

Thrombosis research 20150828 5

<h4>Background</h4>Integrin β3 is involved in tumor and endothelial cell biology as well as in platelet aggregation. Herein, we evaluated the predictive potential of three germline single nucleotide polymorphisms (SNPs) in the integrin β3 gene (rs3809865, rs5918 and rs4642) to predict the risk of venous thromboembolism (VTE) in colorectal cancer (CRC) patients, which is one of the leading causes of death among cancer patients.<h4>Methods</h4>112 patients diagnosed with CRC enrolled in the prospe ...[more]

PMID: 26440977

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Project description:BackgroundVenous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease.MethodsWe included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations.ResultsA total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (P-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23-2.89; P=0.004) and 2.70-fold (95% CI, 1.81-4.06; P<0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29-68) increased risk of VTE (P<0.0001).ConclusionsIn a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.

Project description:Importance:Although malignancy is an established risk factor for venous thromboembolism (VTE), the risk of VTE specifically in patients with keratinocyte carcinoma (KC) has not been previously studied. Objective:To determine the risk of VTE in patients with KC compared with patients not diagnosed with cancer and with patients diagnosed with common malignant neoplasms associated with VTE. Design, Setting, and Participants:Population-based retrospective analysis of patient insurance claims made between January 1, 2007, and December 31, 2014, from the Truven MarketScan Commercial and Medicare Supplemental Databases. Patients treated across the United States were divided into 3 cohorts: patients with KC, patients with pancreatic cancer or acute myelogenous leukemia who are thus at high risk for VTE, and patients without a history of common malignant neoplasms. Patients were excluded from the KC cohort if they had a history of another type of cancer. Data were analyzed between April 1, 2017, and January 15, 2018. Main Outcomes and Measures:Diagnosis of VTE within 1 year following the index date (for the KC and high-risk cohorts, the date of the initial diagnosis of cancer; for the control cohort, the date following 365 days of continuous insurance enrollment). Logistic regression was used to assess the risk of VTE in the KC cohort compared with the high-risk and control cohorts before and after matching across patient characteristics and known risk factors for VTE. Results:Of 5 753 613 potentially eligible patients, the final sample consisted of 740 246 patients (12.8%) across 3 cohorts. Of the 740 246 study participants, 417 839 were in the KC cohort (223 986 [53.6%] men, mean [SD] age, 64.2 [13.6] years); 314 736 were in the control cohort (135 203 [43.0%] men, 42.9 [15.2] years); and 7671 were in the high-risk cohort (3502 [45.7%] men, 59.4 [14.4] years) The risk of VTE in the KC cohort was lower compared with the high-risk cohort in univariable analysis (odds ratio [OR], 0.22; 95% CI, 0.20-0.23; P < .001), multivariable analysis (OR, 0.29; 95% CI, 0.26-0.32; P < .001), and after matching across patient characteristics and known risk factors (OR, 0.52; 95% CI, 0.35-0.78; P = .001). The risk of VTE in the KC cohort was higher in the univariable analysis (OR, 2.31; 95% CI, 2.23-2.41; P < .001), lower in the multivariable analysis (OR, 0.85; 95% CI, 0.80-0.90; P < .001), and not different after matching of patient characteristics and risk factors (OR, 0.95; 95% CI, 0.89-1.01; P = .08) than that of the control cohort. Conclusions and Relevance:The results of this study provided no evidence supporting the increased risk of VTE in the KC cohort compared with the control cohort. Given the inherent risks of chemoprophylaxis, the need for prophylactic anticoagulation in patients with KC who are scheduled for surgery should be carefully considered. Level of Evidence:NA.

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.

Dataset Information

Integrin beta-3 genetic variants and risk of venous thromboembolism in colorectal cancer patients.

Publications

Integrin beta-3 genetic variants and risk of venous thromboembolism in colorectal cancer patients.

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