Prediction of primary venous thromboembolism based on clinical and genetic factors within the U.K. Biobank.
Ontology highlight
ABSTRACT:
SUBMITTER: Kolin DA
PROVIDER: S-EPMC8560817 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism, and a combination of environmental and genetic risk factors contributes to VTE risk. Within environmental risk factors, some are provoking (e.g., cancer, surgery, trauma or fracture, immobilization, pregnancy and the postpartum period, long-distance travel, hospitalization, catheterization, and acute infection) and others are nonprovoking (e.g., age, sex, race/ethnicity, body mass index and obesity, oral contraceptive or hormone therapy use, corticosteroid use, statin use, diet, physical activity, sedentary time, and air pollution). Additionally, VTE has a strong genetic basis, with approximately 50 to 60% of the variance in VTE incidence attributed to genetic effects. Some genetic susceptibility variants that contribute to risk have been identified in candidate genes, mostly related to the clotting system and responsible for inherited hypercoagulable states (e.g., factor V Leiden, prothrombin, fibrinogen gamma, or blood group non-O). Other susceptibility single-nucleotide polymorphisms have been identified from genome-wide association studies, such as the two new loci in TSPAN15 (rs78707713) and SCL44A2 (rs2288904) genes. Risk factors are not always associated with VTE in isolation; however, and an understanding of how environmental and genetic factors interact may provide insight into the pathophysiology of VTE, possibly identifying opportunities for targeted prevention and treatment.
| S-EPMC5146955 | biostudies-literature
Project description:Background Venous thromboembolism (VTE) is highly heritable (estimated heritability [h(2)]=0.62) and likely to be a result of multigenic action.Objective To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE.Methods Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age- and sex- matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n=12296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke.ResultsAmong 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR=1.68, P-value=8.08×10(-16) ) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40.ConclusionsAnticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European ancestry.
| S-EPMC3110632 | biostudies-literature
Project description:A single genetic biomarker is unable to accurately predict the risk for venous thromboembolism (VTE) recurrence. We aimed to: (a) develop a multiple single nucleotide polymorphisms (SNPs) model to predict the risk of VTE recurrence and (b) validate a previously described genetic risk score (GRS) and compare its performance with the model developed in this study. Twenty-two SNPs, including established and putative SNPs associated with VTE risk, were genotyped in the Malmö thrombophilia study cohort (MATS; n = 1465, follow-up ~ 10 years) by using TaqMan PCR. Out of 22-SNPs, 12 had an association with the risk of VTE recurrence and were included for calculating GRSs. The risk of VTE recurrence was calculated by stratifying patients according to number of risk alleles. In 12-SNP GRS, patients with ≥ 7 risk alleles were associated with higher risk of VTE recurrence compared to patients having ≤ 6 risk alleles. In a simplified model (8-SNP GRS), the discriminative power of 8-SNP GRS was similar to that of 12-SNP GRS based on post-test probabilities (PP). Furthermore, 8-SNP GRS further improved the risk prediction of VTE recurrence in unprovoked VTE and male patients (PP% = 15.4 vs 8.3, 17.1 vs 7.2 and 19.0 vs 7.1 for high risk groups vs low risk groups in whole population, males and unprovoked VTE patients respectively). In addition, we also validated previously described 5-SNP GRS in our cohort and found that the 8-SNP GRS performed better than the 5-SNP GRS in terms of higher PP. Our results show that a multiple SNP GRS consisting of 8-SNPs may be an effective model for prediction of VTE recurrence, particularly in unprovoked VTE and male patients.
| S-EPMC6394443 | biostudies-literature
Project description:ImportanceThe risk of venous thromboembolism (VTE) in ambulatory COVID-19 is controversial. In addition, the association of vaccination with COVID-19-related VTE and relevant clinical and genetic risk factors remain to be elucidated.ObjectiveTo quantify the association between ambulatory COVID-19 and short-term risk of VTE, study the potential protective role of vaccination, and investigate clinical and genetic risk factors for post-COVID-19 VTE.Design, setting, and participantsThis population-based cohort study of patients with COVID-19 from UK Biobank included participants with SARS-CoV-2 infection that was confirmed by a positive polymerase chain test reaction result between March 1, 2020, and September 3, 2021, who were then propensity score matched to COVID-19-naive people during the same period. Participants with a history of VTE who used antithrombotic drugs (1 year before index dates) or tested positive in hospital were excluded.ExposuresFirst infection with SARS-CoV-2, age, sex, ethnicity, socioeconomic status, obesity, vaccination status, and inherited thrombophilia.Main outcomes and measuresThe primary outcome was a composite VTE, including deep vein thrombosis or pulmonary embolism, which occurred 30 days after the infection. Hazard ratios (HRs) with 95% CIs were calculated using cause-specific Cox models.ResultsIn 18 818 outpatients with COVID-19 (10 580 women [56.2%]; mean [SD] age, 64.3 [8.0] years) and 93 179 matched uninfected participants (52 177 women [56.0%]; mean [SD] age, 64.3 [7.9] years), the infection was associated with an increased risk of VTE in 30 days (incidence rate of 50.99 and 2.37 per 1000 person-years for infected and uninfected people, respectively; HR, 21.42; 95% CI, 12.63-36.31). However, risk was substantially attenuated among the fully vaccinated (HR, 5.95; 95% CI, 1.82-19.5; interaction P = .02). In patients with COVID-19, older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 1.87 (95% CI, 1.50-2.33) per 10 years, 1.69 (95% CI, 1.30-2.19), and 1.83 (95% CI, 1.28-2.61), respectively. Further, inherited thrombophilia was associated with an HR of 2.05 (95% CI, 1.15-3.66) for post-COVID-19 VTE.Conclusions and relevanceIn this population-based cohort study of patients with COVID-19, ambulatory COVID-19 was associated with a substantially increased risk of incident VTE, but this risk was greatly reduced in fully vaccinated people with breakthrough infection. Older age, male sex, and obesity were clinical risk factors for post-COVID-19 VTE; factor V Leiden thrombophilia was additionally associated with double the risk, comparable with the risk of 10-year aging. These findings may reinforce the need for vaccination, inform VTE risk stratification, and call for targeted VTE prophylaxis strategies for unvaccinated outpatients with COVID-19.
| S-EPMC9389434 | biostudies-literature
Project description:ObjectiveClinical prediction rules (CPRs) followed by D-dimer testing were shown to safely rule out venous thromboembolism (VTE) in about half of all suspected patients in controlled and experienced study settings. Yet, its real-life impact in primary care is unknown. The aim of this study was to determine the real-life impact of CPRs for suspected VTE in primary care.DesignCross-sectional cohort study.SettingPrimary care in the Netherlands.ParticipantsPatients with suspected deep venous thrombosis (n=993) and suspected pulmonary embolism (n=484).InterventionsGeneral practitioners received an educational instruction on how to use CPRs in suspected VTE. We did not rectify incorrect application of the CPR in order to mimic daily clinical care.Main outcome measuresPrimary outcomes were the diagnostic failure rate, defined as the 3-month incidence of VTE in the non-referred group, and the efficiency, defined as the proportion of non-referred patients in the total study population. Secondary outcomes were determinants for and consequences of incorrect application of the CPRs.ResultsIn 267 of the included 1477 patients, VTE was confirmed. When CPRs were correctly applied, the failure rate was 1.51% (95% CI 0.77 to 2.86), and the efficiency was 58.1% (95% CI 55.2 to 61.0). However, the CPRs were incorrectly applied in 339 patients, which resulted in an increased failure rate of 3.31% (95% CI 1.07 to 8.76) and a decreased efficiency of 35.7% (95% CI 30.6 to 41.1). The presence of concurrent heart failure increased the likelihood of incorrect application (adjusted OR 3.26; 95% CI 1.47 to 7.21).ConclusionsCorrect application of CPRs for VTE in primary care is associated with an acceptable low failure rate at a high efficiency. Importantly, in nearly a quarter of patients, the CPRs were incorrectly applied that resulted in a higher failure rate and a considerably lower efficiency.
| S-EPMC7772307 | biostudies-literature
Project description:To investigate the possible predictive role of routinely used glycemic parameters for a first venous thromboembolism (VTE) episode in gastrointestinal (GI) cancer ambulatory patients - with or without clinically diagnosed type 2 diabetes (T2D) or obesity - treated with chemotherapy.Pre-treatment fasting blood glucose, insulin, glycated hemoglobin (HbA1c) and homeostasis model of risk assessment (HOMA) were retrospectively evaluated in a cohort study of 342 GI cancer patients. Surgery was performed in 142 (42%) patients with primary cancer, 30 (21%) and 112 (79%) of whom received neoadjuvant and adjuvant therapies, respectively. First-line chemotherapy was administered in 200 (58%) patients with metastatic disease. The study outcome was defined as the occurrence of a first symptomatic or asymptomatic VTE episode during active treatment.Impaired glucose tolerance (IGT) or T2D were diagnosed in 30% of GI cancer patients, while overweight/obesity had an incidence of 41%. VTE occurred in 9.4% of patients (7% of non-diabetic non-obese), especially in those with a high ECOG score (P = 0.025). No significant association was found between VTE incidence and T2D, obesity, different tumor types, metastatic disease, Khorana class of risk, or different anti-cancer drugs, although VTE rates were substantially higher in patients receiving bevacizumab (17% vs 8%, P = 0.044). Conversely, all glucose metabolic indexes were associated with increased VTE risk at ROC analysis. Multivariate Cox proportional analyses confirmed that HOMA index (HR = 4.13, 95%CI: 1.63-10.5) or fasting blood glucose (HR = 3.56, 95%CI: 1.51-8.39) were independent predictors of VTE occurrence during chemotherapy.The results here reported demonstrate that evaluating glucose metabolic asset may allow for VTE risk stratification in GI cancer, helping to identify chemotherapy-treated patients who might benefit from thromboprophylaxis. Further multicenter prospective studies involving a larger number of patients are presently needed.
| S-EPMC5537185 | biostudies-other
Project description:Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. We studied 134 patients with VTE separated into 3 groups: (1) ‘low-risk’ patients had ≥1 provoked VTE; (2) ‘moderate-risk’ patients had no more than 1 unprovoked VTE; (3) ‘high-risk’ patients had ≥2 unprovoked VTE. 44 individuals with no history of VTE were enrolled as healthy controls. Consented individuals were enrolled at 4 medical centers in the US. Total RNA from whole blood was isolated and hybridized to Illumina HT-12 V4 Beadchips to assay whole genome expression. Using class prediction analysis, we distinguished high-risk patients from healthy controls with good receiver operating curve characteristics (AUC=0.88). We also distinguished high-risk from low-risk individuals, moderate-risk individuals from healthy controls, and low-risk individuals from healthy controls with AUC’s of 0.72, 0.77 and 0.72, respectively. Using differential expression analysis, we identified genes relevant to coagulation, immune response and vascular biology, such as SELP and CD46, which were differentially expressed in at least two comparisons. Neither approach distinguished the moderate-risk patients from the high-risk or low-risk groups. Gene expression profiles may provide insights into biological mechanisms associated with patients at risk for recurrent VTE. Prospective studies are needed to validate these findings.
2015-11-23 | GSE48000 | GEO
Project description:Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. We studied 134 patients with VTE separated into 3 groups: (1) âlow-riskâ patients had â¥1 provoked VTE; (2) âmoderate-riskâ patients had no more than 1 unprovoked VTE; (3) âhigh-riskâ patients had â¥2 unprovoked VTE. 44 individuals with no history of VTE were enrolled as healthy controls. Consented individuals were enrolled at 4 medical centers in the US. Total RNA from whole blood was isolated and hybridized to Illumina HT-12 V4 Beadchips to assay whole genome expression. Using class prediction analysis, we distinguished high-risk patients from healthy controls with good receiver operating curve characteristics (AUC=0.88). We also distinguished high-risk from low-risk individuals, moderate-risk individuals from healthy controls, and low-risk individuals from healthy controls with AUCâs of 0.72, 0.77 and 0.72, respectively. Using differential expression analysis, we identified genes relevant to coagulation, immune response and vascular biology, such as SELP and CD46, which were differentially expressed in at least two comparisons. Neither approach distinguished the moderate-risk patients from the high-risk or low-risk groups. Gene expression profiles may provide insights into biological mechanisms associated with patients at risk for recurrent VTE. Prospective studies are needed to validate these findings. This study includes a total of 218 samples/individuals (in 5 groups; APS, high-risk VTE, moderate-risk VTE, low-risk VTE and healthy-controls). Samples in which the percent of probes present was 15% or less (n=51) were excluded leaving 167 samples. The data for these 167 samples were normalized together. However, this record represents the 132 individual samples in the following groups; high-risk (n=40); moderate-risk (n=33); low-risk (n=34); and healthy controls (n=25). The 35 samples in APS group are represented in GSE48001.
2015-11-23 | E-GEOD-48000 | biostudies-arrayexpress
Project description:BackgroundKlinefelter syndrome (KS) is one of the commonest sex chromosome disorders. Affected males become infertile and highly susceptible to several health problems, including vascular thromboembolism (VTE). The risk of VTE may be exacerbated by an underlying genetically inherited thrombophilia. In this study, we aimed to investigate the genotype and allele frequencies of common gene polymorphisms related to hereditary thrombophilia in infertile males with KS compared to normal, fertile men.MethodsEighty-five infertile males with KS and 75 healthy control males were included in this case-control study. Genetic testing was done using an extended thrombophilia gene panel by Multiplex PCR reverse hybridization method.ResultsThere was an increased frequency of mutant alleles and heterozygous genotypes of FV Leiden, FV H 1299R, Pro G20210A, MTHFR C677T and PAI-1 4G/5G thrombophilic gene polymorphisms in KS patients compared to the control group. It was shown that 10.7% of KS patients had the A3 haplotype of the EPCR gene in comparison to 5.3% of control patients. The A3/A3 genotype was found only in KS patients (7.1%). Carriers of more than one mutant allele in KS patients exceeded the control (p < 0.001).ConclusionA high prevalence of thrombophilic gene polymorphisms and the coexistence of different mutant alleles were evident in infertile KS males. These data highlight the importance of conducting further studies to understand the role of hereditary thrombophilia in predicting venous thrombosis in patients with Klinefelter syndrome.
| S-EPMC7303976 | biostudies-literature
Project description: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.
| S-EPMC2693946 | biostudies-literature