Search

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis. Methods: To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45–65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite–HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test. Results: Our analyses revealed that 118 metabolites were univariately associated with HTGC (p-value

Contains fulltext : 293489.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. METHODS: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. RESULTS: A total of 6112 participants with a median age of 69 years (interquartile range, 65-74) and median of 2 (interquartile range, 1-3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87-1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46-1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35-1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66-1.28). DISCUSSION: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs. 01 juni 2023

Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (

Background Oral postmenopausal hormone therapy (HT) increases the risk of venous thrombosis (VT). We postulated that activated protein C (APC) resistance induced by HT is one of the mechanisms causing VT, and also assessed the role of one of the main determinants of APC resistance, i.e., tissue factor pathway inhibitor (TFPI). Methods We performed a nested case-control study embedded within two Women's Health Initiative (WHI) hormone trials. Women were randomized to hormone therapy or placebo. Biomarkers were measured at baseline and after one-year, in 217 cases and 817 controls. Results Increased APC resistance and decreased TFPI at baseline were associated with VT (OR ranging from 1.20 to 2.06). However, women with such prothrombotic profile at baseline did not have further increased risk of VT when randomized to HT compared with placebo. While there was no change in APC resistance or TFPI in placebo group after one-year, HT group showed prothrombotic changes in the biomarkers, i.e., an increase in APC resistance (mean(sd):0.39 (0.54)) and decrease in TFPI (-0.21(0.50): free TFPI, -0.24(0.22): TFPI activity and -0.22(0.20): total TFPI). However, HT induced prothrombotic change in biomarkers did not increase risk of VT. Conclusion Women with prothrombotic levels of APC resistance and TFPI at baseline were not at increased risk of VT when randomized to HT compared with placebo. This suggests that testing for these biomarkers prior to starting HT is not required. HT led to prothrombotic change in these biomarkers after one year, but this did not relate to increased risk of VT.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

It is not known whether the synergistic effect of genetic markers, increasing the risk of venous thrombosis (VT), and combined oral contraceptives (COC) use varies between different types of progestogens in these preparations. We investigated the joint effect of genetic risk factor, that is, F5 rs6025, F2 rs1799963, and FGG rs2066865 mutations, and different progestogens on the risk of VT. The constrained maximum likelihood estimation (CMLE) method was used to calculate joint effects, expressed as odds ratio (OR) with 95% confidence intervals [CI]. As the dose of estrogen is known to be a risk factor for VT, analyses were restricted to COC with 30 mu g estrogen and each progestogen. Overall, the joint effect of COC and genetic variants was lowest for COC containing the progestogen levonorgestrel, albeit CIs were wide. The OR (95% CI) of the four different analyses (i.e. joint effect with F5 rs6025, F2 rs1799963, F5 rs6025 or F2 rs1799963 and FGG rs2066865) ranged between 7 center dot 4 (5 center dot 4-10 center dot 2) and 24 center dot 8 (12 center dot 3-50 center dot 0) for levonorgestrel. For gestodene the joint effect ranged between 11 center dot 7 (7 center dot 2-19 center dot 1) and 30 center dot 9 (10 center dot 6-89 center dot 9). Desogestrel and cyproterone acetate had the highest risk estimates: 14 center dot 6 (9 center dot 7-21 center dot 9) and 32 center dot 6 (13 center dot 2-80 center dot 6) and 15 center dot 5 (9 center dot 7-24 center dot 9) and 44 center dot 4 (16 center dot 9-116 center dot 3) respectively. In women with inherited thrombophilia, COC containing levonorgestrel were associated with the lowest risk of VT, albeit the CIs were wide.

In thrombin generation (TG) assays, regarded as global coagulation tests, contact activation is considered a major problem which can be eliminated by adding Corn Trypsin Inhibitor (CTI). In previous studies, however, venous thrombosis risk prediction using TG assays did not improve after CTI addition. However, it is unknown whether CTI addition could help to detect subtle but relevant nuances in determinants of TG, making the assay more suitable to detect disturbances in the coagulation system. This study’s objective was to assess whether the addition of CTI is associated with a broader contribution of individual coagulation factors to the total amount of thrombin formed in Calibrated Automated Thrombogram (CAT) and Technoclone Thrombin Generation Assay (TGA). Thrombin generation was measured in 326 healthy individuals from THE VTE study at very low tissue factor concentrations, with and without addition of CTI prior to blood sampling. The influence of several coagulation factors on total amount of thrombin formed, i.e. area under the curve (AUC) or endogenous thrombin potential (ETP), was analysed using multiple linear regression with standardisation of all values resulting in Z-scores with 95% confidence intervals (95%CI). Association between coagulation factors and TG changed minimally after addition of CTI. Largest changes after CTI addition were found for following factors: for CAT: free protein S (from 0.00 (95%CI -0.12 to 0.12) to -0.29 (95%CI -0.43 to -0.15)) and protein S (from -0.05 (95%CI -0.18 to 0.08) to -0.21 (95%CI -0.37 to -0.05)); for TGA: antithrombin (from -0.11 (-0.23 to 0.02) to -0.19 (-0.30 to -0.07)), factor VIII (from 0.15 (0.03 to 0.27) to 0.24 (0.13 to 0.36)) and fibrinogen (from 0.12 (-0.01 to 0.26) to 0.19 (0.06 to 0.32)). In conclusion, there is no clear trend towards a broader contribution of coagulation factors in samples handled with CTI compared with those handled without CTI.

Men seem to have a higher intrinsic risk of venous thromboembolism (VTE) than women, regardless of age. To date, this difference has not been explained. By integrating state-of-the-art research presented at the International Society on Thrombosis and Haemostasis Congress of 2021 with the available literature, we address potential explanations for this intriguing risk difference between men and women. We discuss the role of exogenous and endogenous sex hormones as the most important known sex-specific determinants of VTE risk. In addition, we highlight clues on the role of sex hormones and VTE risk from clinical scenarios such as pregnancy and the polycystic ovary syndrome. Furthermore, we address new potential sex-specific risk factors and unanswered research questions, which could provide more insight in the intrinsic risk difference between men and women, such as body height and differences in body fat distribution, leading to dysregulation of metabolism and inflammation.

In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. In an ambispective design, when the risk factors studied are independent of time, including both pre- and post-inclusion events in the analyses increases the statistical power but may lead to a selection bias. To avoid such a bias, we propose a survival analysis weighted by the inverse of the survival probability at the time of data collection about the events.This method is applied to the study of the association of ABO blood groups with the risk of venous thromboembolism (VT) recurrence in the MARTHA and MEGA cohorts. The former relying on an ambispective design and the latter on a standard prospective one. In the combined sample totalling 2,752 patients including 993 recurrences, compared with the O1 group, A1 has an increased risk (Hazard Ratio (HR) of 1.18, p=4.2×10−3), homogeneously in MARTHA and in MEGA. The same trend (HR=1.19, p=0.06) was observed for the less frequent A2 group.In conclusion, this work clarified the association ofABOblood groups with the risk of VT recurrence. Besides, the methodology proposed here to analyse time-independent risk factors of events in an ambispective design has an immediate field of application in the context of genome wide association studies.

Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm–transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: −6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10−8]) located in the ABO gene reached genome-wide significant level (P < 5 × 10−8) and was also replicated successfully (β: −7.8% [MAF 0.32, P = 7.2 × 10−5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.

Background A high D‐dimer level and parameters of the thrombin generation (TG) potential are associated with the risk of a first venous thrombosis (VT) in young and middle‐aged populations. Objectives To investigate whether D‐dimer and TG potential (lag‐time, time‐to‐peak [ttPeak], peak thrombin, endogenous thrombin potential [ETP], and velocity index), are associated with the risk of a first VT in those aged 70 years and older. Methods We included 215 patients with a first VT and 358 controls, all aged >70 years, from the Age and Thrombosis, Acquired and Genetic Risk Factors in the Elderly (AT‐AGE) study. To assess the risk of VT, odds ratios with 95% confidence intervals (CIs) were estimated using logistic regression analysis. Results D‐dimer and all TG parameters except lag time were associated with an increased risk of VT in a dose‐response manner. Comparing the fourth with the first quartile (for ttPeak comparing the first with the fourth quartile), risk estimates were: 7.8 (95% CI, 4.0‐15.0) for peak, 2.0 (95% CI, 1.2‐3.3) for ttPeak, 9.1 (95% CI, 4.4‐18.9) for ETP, and 11.5 (95% CI, 5.7‐23.3) for velocity index. Comparing the highest quartile of D‐dimer with the lowest, the risk was 7.7‐fold increased (95% CI, 4.0‐14.8). Furthermore, all factors also increased the risk of VT after dichotomizing at more extreme cutoff values. The risk of VT was further increased in the presence of multiple prothrombotic TG parameters and elevated D‐dimer level or in combination with prothrombotic mutations. Conclusions D‐dimer and TG parameters (except lag time) are associated with the risk of first VT in elderly population.

Background Venous thromboembolism (VTE) is a complex disease with an incidence rate of about 1 in 1000 per year. Despite the availability of validated biomarkers for VTE, unprovoked events account for 50% of first events. Therefore, emerging high‐throughput proteomics are promising methods for the expansion of VTE biomarkers. One such promising high‐throughput platform is SomaScan, which uses a large library of synthetic oligonucleotide ligands known as aptamers to measure thousands of proteins. Objective The aim of this study was to evaluate the viability of the aptamer‐based SomaScan platform for VTE studies by examining its agreement with standard laboratory methods. Methods We examined the agreement between eight established VTE biomarkers measured by SomaScan and standard laboratory immunoassay and viscosity‐based instruments in 54 individuals (27 cases and 27 controls) from the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism study. We performed the agreement analysis by using a regression model and predicting the estimates and the 95% prediction interval (PI) of the laboratory instrument values using SomaScan values. Results SomaScan measurements exhibited overall poor agreement, particularly for D‐dimer (average fit, 492.7 ng/mL; 95% PI, 110.0‐1998.2) and fibrinogen (average fit, 3.3 g/L; 95% PI, 2.0‐4.7). Conclusion Our results indicate that SomaScan measurement had poor agreement with the standard laboratory measurements. These results may explain why some genome‐wide association studies with VTE proteins measured by SomaScan did not confirm previously identified loci. Therefore, SomaScan should be considered with caution in VTE studies.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

International audience; In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research(1) aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy.

Background Von Willebrand factor (VWF) levels are regulated by genetic and acquired factors. The acquired factors are mostly related to age and could be mediators of the age effect on VWF levels. Objectives To disentangle the role of genetic (sex, blood group) and acquired factors (comorbidities, body mass index, reduced kidney function, hormone use, and inflammation) in regulating von Willebrand factor antigen (VWF:Ag) and factor VIII activity (FVIII:C) levels in the normal population. Methods Analysis were performed in a large population sample (2923 individuals) from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), after exclusion of individuals with active cancer and women who were pregnant or within nine months postpartum. The increase of VWF:Ag and FVIII:C with age was evaluated by linear regression after the age of 40 years. Analyses were adjusted for acquired factors and stratified for sex and blood group. Results VWF:Ag and FVIII:C increased with age: increase per decade of age for VWF:Ag 18 IU/dL (95%CI 15–20) and for FVIII:C 12 IU/dL (95%CI 10–14). After adjustment for acquired factors, the increase per decade was 13 IU/dL (95%CI 10–16) for VWF:Ag and 9 IU/dL (95%CI 6–11) for FVIII:C. The stratified analysis for blood group showed higher increase in the non-O group, but these differences were annulled after adjustment for acquired factors. Conclusions VWF:Ag and FVIII:C increase with age. Carriers of blood group non-O present a steeper increase of VWF:Ag and FVIII:C with age, that is mediated by acquired factors.

Essentials Venous thrombosis (VT) risk and coagulation factor levels increase with age. We studied the association between levels of procoagulant factors and the risk of a first VT in the elderly. Higher levels of factors VIII, IX, and XI, but not prothrombin, were associated with the risk of VT. Similar risk patterns were observed for provoked and unprovoked VT and for deep vein thrombosis and pulmonary embolism separately. ABSTRACT: Background Venous thrombosis (VT) incidence increases markedly with age. Coagulation factors are also positively associated with age. Objective To study whether higher levels of coagulation factors II (prothrombin), VIII, IX, and XI are associated with risk of a first VT in the elderly. Methods Four hundred and one patients and 431 control subjects aged 70 and older were included in the Age and Thrombosis, Acquired and Genetic risk factors in the Elderly (AT-AGE) study. Blood was collected 1 year after the event in patients and in all control subjects for measurement of coagulation factors. To assess the risk of VT, odds ratios (ORs) were calculated after stratification of coagulation factors in quartiles and at the 90th percentile, adjusting for potential confounders (age, sex, body mass index, and study center). Results Mean age was 78 years (range: 70-100 years). The ORs of VT for factors in the top quartile compared with the lowest quartile were 4.5 (95% confidence interval [CI]:2.7-7.3) for factor VIII, 2.4 (95% CI:1.1-5.2) for factor IX, and 1.7 (95% CI:1.0-2.9) for factor XI. High prothrombin was not associated with an increased VT risk. There was no dose-response association between the number of high coagulation factors and VT risk. The population attributable risk (PAR) of VT was 37.6%, 23.3%, and 12.4% for factor VIII, IX, and XI, respectively. Conclusion In this study of the elderly, higher factors VIII, IX, and XI but not prothrombin, were positively associated with the risk of VT.

Metabolomics studies have seen a steady growth due to the development and implementation of affordable and high-quality metabolomics platforms. In large metabolite panels, measurement values are frequently missing and, if neglected or sub-optimally imputed, can cause biased study results. We provided a publicly available, user-friendly R script to streamline the imputation of missing endogenous, unannotated, and xenobiotic metabolites. We evaluated the multivariate imputation by chained equations (MICE) and k-nearest neighbors (kNN) analyses implemented in our script by simulations using measured metabolites data from the Netherlands Epidemiology of Obesity (NEO) study (n = 599). We simulated missing values in four unique metabolites from different pathways with different correlation structures in three sample sizes (599, 150, 50) with three missing percentages (15%, 30%, 60%), and using two missing mechanisms (completely at random and not at random). Based on the simulations, we found that for MICE, larger sample size was the primary factor decreasing bias and error. For kNN, the primary factor reducing bias and error was the metabolite correlation with its predictor metabolites. MICE provided consistently higher performance measures particularly for larger datasets (n &gt, 50). In conclusion, we presented an imputation workflow in a publicly available R script to impute untargeted metabolomics data. Our simulations provided insight into the effects of sample size, percentage missing, and correlation structure on the accuracy of the two imputation methods.

The risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE), the androgenic progestogens are better able to counteract the EE-induced stimulation of liver proteins and hence are associated with a twofold decreased risk of VT compared with non- or antiandrogenic progestogens, which exert limited counteraction of EE. Because EE is responsible for the increased risk, novel estrogens such as estradiol were developed and seem to have a lower risk of VT than EE. Besides COCs, there are other methods of hormonal contraceptives, such as progestogen-only contraceptives, which do not increase VT risk, except for injectables. Other nonoral contraceptives are combined vaginal rings and patches. There is insufficient evidence regarding the risk of VT associated with these two methods compared with COCs. The increased risk associated with COCs is more pronounced in women with inherited thrombophilia. In these women, the progestogen levonorgestrel seems to be associated with the lowest risk of VT. Currently, there are no studies that have investigated the risk of VT in women who switch COCs. We hypothesize that switching COCs, even when switching from a high- to a low-risk COC, increases the risk of VT. Finally, risk prediction models in women who use COCs are lacking. Since there is a large number of VT cases associated with COC use, it is important to identify women at risk of VT and advise them on alternative contraception methods.

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

Background: Cholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism. Previous studies have suggested that the CETP TaqI B1/B2 allele is associated with the risk of venous thrombosis (VT).Aim: To investigate the associations between genetically determined CETP concentrations and 22 hemostatic factors in healthy individuals, and the risk of a first VT event, in a large VT case-control study.Methods: Analyses were performed in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) case-control study. CETP unweighted/weighted genetic risk scores (GRSs) were derived from three single-nucleotide polymorphisms that were identified from a recent genome-wide association study on serum CETP concentrations. The associations between CETP GRSs and 22 hemostatic factors (procoagulant/anticoagulant and fibrinolytic factors) were assessed by linear regression from an additive model in controls (n = 2813). The associations between CETP GRSs and the risk of a first VT were assessed by logistic regression analyses in 3950 VT cases and 4765 controls.Results: In the controls (median age, 49 years; 53% women), both unweighted and weighted GRSs showed that factor VII activity was negatively associated with the genetically determined CETP concentration (weighted GRS β -3.08 IU/dL per μg/mL genetically determined CETP, 95% confidence interval -5.73 to -0.42). No association was observed with the risk of a first VT.Conclusions: Genetically determined CETP concentrations only showed a weak negative association with factor VII activity. However, this did not lead to an association with the risk of a first VT.

Background Use of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels. Methods Premenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study. Results Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (OR LETS : 3.78; OR MEGA : 2.61) as well as SHBG levels (mean difference 27.6 nmol/L, 95%CI: − 61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis. Conclusion Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users.

Background The risk of venous thromboembolism (VTE) in young women can predominantly be attributed to exogenous hormone use. The influence of (abnormalities in) endogenous sex hormones, as in polycystic ovary syndrome (PCOS) or primary ovarian insufficiency (POI), on VTE risk is uncertain. Objectives Th assess the association between endogenous sex hormone levels and VTE risk. Methods Women aged ≤45 years from the MEGA case‐control study who provided a blood sample in the absence of exogenous hormone exposure or pregnancy were included. Sex hormone–binding globulin (SHBG), estradiol, follicle‐stimulating hormone (FSH) and testosterone were measured. The free androgen index (FAI) and estradiol to testosterone ratio (E:T) were calculated. VTE risk was assessed according to quartiles (Qs) of levels and clinical cut‐offs as proxies for PCOS (FAI > 4.5) and POI (FSH > 40 U/L). Logistic regression models were used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Results Six hundred and sixty‐five women (369 cases; 296 controls) were eligible for the analyses. Testosterone and FSH levels, E:T and POI (FSH > 40 U/L vs FSH ≤ 40 U/L) were not associated with VTE risk. For estradiol, VTE risk was increased with levels in Q4 vs Q1 (OR 1.6; 95% CI 1.0‐2.5). There was a dose‐response relationship between SHBG levels and VTE risk, with the highest OR at Q4 vs Q1: 2.0 (95% CI 1.2‐3.3). FAI > 4.5 (PCOS proxy) vs FAI ≤ 4.5 was associated with increased VTE risk (OR 3.3; 95% CI 0.9‐11.8). Conclusions Estradiol, SHBG and FAI were associated with VTE risk, suggesting a role for endogenous sex hormones in the pathophysiology of VTE in young women.

The measurement of homocysteine is still part of routine thrombosis or thrombophilia work-up in many thrombosis centres in the world. Previous observational studies have shown that hyperhomocysteinaemia is associated with an increased risk of first and recurrent venous thrombosis (VT). Randomised trials, however, showed no benefit of homocysteine-lowering therapy on the risk of first or recurrent VT. This discrepancy could be explained by incomplete adjustment for confounders in the observational studies. We investigated in a large population-based follow-up study whether if the levels of homocysteine and its metabolites, methionine and cysteine, were associated with recurrent VT. Approximately three months after discontinuation of anticoagulant treatment, homocysteine, methionine and cysteine concentrations were measured in 2210 patients with VT. During a median follow-up of 6 center dot 9 years, 340 patients developed a recurrence (incidence rate, 2 center dot 8/100 patient-years). We found that elevated homocysteine concentrations were not associated with an increased risk of recurrent VT, neither as a continuous variable per 5 mu mol/l increase (hazard ratio [HR] 0 center dot 98 (95% confidence interval [CI], 0 center dot 90-1 center dot 04)) nor when levels were >95th (>23 center dot 0 mu mol/l) percentile (HR 1 center dot 03 (95% CI, 0 center dot 65-1 center dot 64)). Similar results were obtained for cysteine and methionine values. We conclude that hyperhomocysteinaemia is not associated with an increased risk of recurrent VT.

Background Recurrent venous thromboembolism (VTE) is common. Current guidelines suggest that patients with unprovoked VTE should continue anticoagulants unless they have a high bleeding risk, whereas all others can stop. Prediction models may refine this dichotomous distinction, but existing models apply only to patients with unprovoked first thrombosis. We aimed to develop a prediction model for all patients with first VTE, either provoked or unprovoked. Methods and findings Data were used from two population-based cohorts of patients with first VTE from the Netherlands (Multiple Environment and Genetic Assessment of Risk Factors for Venous Thrombosis [MEGA] follow-up study, performed from 1994 to 2009; model derivation; n = 3,750) and from Norway (Tromsø study, performed from 1999 to 2016; model validation; n = 663). Four versions of a VTE prediction model were developed: model A (clinical, laboratory, and genetic variables), model B (clinical variables and fewer laboratory markers), model C (clinical and genetic factors), and model D (clinical variables only). The outcome measure was recurrent VTE. To determine the discriminatory power, Harrell’s C-statistic was calculated. A prognostic score was assessed for each patient. Kaplan-Meier plots for the observed recurrence risks were created in quintiles of the prognostic scores. For each patient, the 2-year predicted recurrence risk was calculated. Models C and D were validated in the Tromsø study. During 19,201 person-years of follow-up (median duration 5.7 years) in the MEGA study, 507 recurrences occurred. Model A had the highest predictive capability, with a C-statistic of 0.73 (95% CI 0.71–0.76). The discriminative performance was somewhat lower in the other models, with C-statistics of 0.72 for model B, 0.70 for model C, and 0.69 for model D. Internal validation showed a minimal degree of optimism bias. Models C and D were externally validated, with C-statistics of 0.64 (95% CI 0.62–0.66) and 0.65 (95% CI 0.63–0.66), respectively. According to model C, in 2,592 patients with provoked first events, 367 (15%) patients had a predicted 2-year risk of >10%, whereas in 1,082 patients whose first event was unprovoked, 484 (45%) had a predicted 2-year risk of, Suzanne C. Cannegieter and colleagues present a model for predicting repeat venous thromboembolism., Author summary Why was this study done? Patients who suffered from a deep vein thrombosis or pulmonary embolism for the first time have an average risk of 3%–5% per year of having a second event. Such a recurrence can be prevented with anticoagulant treatment, but this should be continued indefinitely, which will lead to a substantial risk of bleeding. The risks of both recurrent thrombosis and bleeding differ substantially between individuals. The choice of continuation on the one hand (with a decreased thrombosis risk but an increased bleeding risk) and discontinuation on the other hand (with an increased thrombosis risk but a decreased bleeding risk) is currently difficult to make for both clinicians and patients. Individual differences in risks are hardly taken into account. What did the researchers do and find? Data were used from two population-based cohorts of patients with first venous thrombosis from the Netherlands (Multiple Environment and Genetic Assessment of Risk Factors for Venous Thrombosis [MEGA] study; n = 3,750) and from Norway (Tromsø study; n = 663). Four versions of a venous thromboembolism (VTE) recurrence risk prediction model were developed in the MEGA data, differing in number and type of included predictors, of which two were validated in the Tromsø study. During 19,201 person-years of follow-up, 507 recurrences occurred. The predictive capability varied between the models. A substantial proportion of patients with a first venous thrombosis are currently misclassified with respect to duration of anticoagulant treatment. What do these findings mean? The prediction model we propose applies to all patients, allows refined risk stratification, and is easily usable. A limitation of both cohorts is that laboratory measurements were missing in a substantial proportion of patients, which were imputed. For optimal individualized treatment, a management study is necessary in which bleeding risks are also taken into account.

Intuitively, researchers do not include subjects who do not have the opportunity to be exposed, such as men in studies on oral contraceptives (OCs). We aimed to explore in which situations it is nevertheless beneficial to do so. We considered the effect of including men in case-control analyses of 8 different hypothetical data sets on the effect of OC use and venous thrombosis. In all scenarios, OC use was the exposure of interest, sex the factor that determined exposure opportunity, and air travel another risk factor. In some of these scenarios, sex and air travel were included as confounders or effect modifiers. Logistic regression was used to estimate odds ratios. Standard errors of the estimated log odds ratios, including and excluding men, were compared. We also studied the effect of including men using data from 1999–2004 from a case-control study on risk factors for venous thrombosis, conducted in the Netherlands. In all hypothetical examples, and in the real-data study, addition of men to the analysis yielded the same odds ratios when correctly adjusting for confounding. Moreover, use of additional subjects often led to more precise estimates. We suggest that subjects who do not have the opportunity to be exposed should not routinely be excluded from epidemiologic studies.

It is unclear whether hyperglycaemia or diabetes mellitus are risk factors for a first venous thrombosis (VT). Self-reported diabetes status and fasting glucose (FG) measures were collected from the Multiple Environmental and Genetic Assessment (MEGA) study to confirm these associations. FG levels were categorized based on the World Health Organization criteria [= 7 center dot 0 (3rd) mmol/l]. Logistic regression was performed to quantify the associations. Neither increased FG levels [Odds ratio (95% confidence interval): 0 center dot 98 (0 center dot 69-1 center dot 37) 2nd vs. reference, 0 center dot 97 (0 center dot 58-1 center dot 63) 3rd vs. reference] nor self-reported diabetes [1 center dot 12 (0 center dot 80-1 center dot 58)] were associated with an increased risk of a first VT.

Background It is insufficiently understood if there is an association between diabetes and VT, and what the underlying mechanism would be. Objectives We aimed to study the association between glucose concentrations with several coagulation factors in the general population. Methods This is a cross-sectional analysis of baseline measurements within 5778 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort study of individuals 45 to 65 years. Associations between fasting glucose and HbA1c concentrations, and postprandial glucose response and factor (F) VIII, FIX, FXI, and fibrinogen levels were examined using linear regression analyses and by calculating mean levels per category of glucose concentrations while adjusting for confounding factors. Results Per each mmol/L higher fasting glucose concentration we observed higher levels of fasting FVIII (5.33%, 95% CI: 4.00-6.65), FIX (6.19%, 95% CI: 5.15-7.23), and FXI (2.11%, 95% CI: 1.20-3.02). Results for fasting HbA1c and postprandial glucose response were similar. Participants with an impaired fasting glucose, high fasting glucose, and diabetes mellitus had higher mean levels of FVIII, FIX, and FXI than those with a normal glucose metabolism, with the highest differences in the levels of FVIII, FIX, and FXI between a high fasting glucose and a normal glucose metabolism. All associations attenuated after adjustment for total body fat, yet all of the above associations remained after adjustment for the confounding factors, except for fibrinogen when contrasted to glucose. Conclusion Concentrations of fasting glucose and HbA1c and postprandial glucose response were positively associated with FVIII, FIX, and FXI, and to some extent also with fibrinogen.

Background Kidney function, measured as estimated glomerular filtration rate (eGFR), glucose levels and haematologic variables (blood cell count) are easily obtainable tests, and have been associated with increased risk of first venous thrombosis (VT). Whether these routine tests can identify patients at risk of recurrence is unclear. Aim Our aim was to investigate the predictive value of serum glucose levels, eGFR and haematologic variables in patients at risk of recurrent VT. Methods Patients with a first VT were followed from discontinuation of anticoagulant treatment. Percentile categories of eGFR, glucose levels and haematologic variables were established. Crude incidence rates with 95% confidence intervals (CIs) of recurrence were estimated in each percentile category. Cox regression models were used to compare groups, adjusted for age and sex. Results Of 2,106 patients followed for a median of 6.9 years, 326 developed recurrence (incidence rate, 2.7/100 patient-years; 95% CI, 2.5–3.1). The adjusted hazard ratio for recurrence was 1.5 (95% CI, 0.9–2.4) in the lowest eGFR percentile category (< 59 mL/min/1.73 m2) versus the reference (≥86 mL/min/1.73 m2). Stratification by unprovoked or provoked first events yielded similar results. The combination of a first unprovoked VT with renal dysfunction was associated with a threefold increased risk of recurrence compared with those with first provoked VT and normal kidney function (hazard ratio, 3.1, 95% CI, 1.6–5.9). Glucose levels and haematologic variables were not associated with increased recurrence risk. Conclusion Testing glucose levels and haematologic variables did not identify patients at increased risk of recurrent VT. Renal dysfunction tests may have some predictive value, particularly in combination with other variables.

Background Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown. Aim To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). Methods We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants. Results We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52–2.73; P = 2.07 × 10−6; Bonferroni P = 0.008). In addition, we identified 8839 rare variants (MAF ≤ 1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT. Conclusion Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT.

Patients at high risk for venous thrombosis (VT) following knee arthroscopy could potentially benefit from thromboprophylaxis. We explored the predictive values of environmental, genetic risk factors and levels of coagulation markers to integrate these into a prediction model. Using a population-based case–control study into the aetiology of VT, we developed a Complete (all variables), Screening (easy to use in clinical practice) and Clinical (only environmental risk factors) model. The Clinical model was transformed into the Leiden-Thrombosis Risk Prediction (arthroscopy) score [L-TRiP(ascopy) score]. Model validation was performed both internally and externally in another case–control study. A total of 4,943 cases and 6,294 controls were maintained in the analyses, 107 cases and 26 controls had undergone knee arthroscopy. Twelve predictor variables (8 environmental, 3 haemorheological and 1 genetic) were selected from 52 candidates and incorporated into the Complete model (area under the curve [AUC] of 0.81, 95% confidence interval [CI], 0.76–0.86). The Screening model (9 predictors: environmental factors plus factor VIII activity) reached an AUC of 0.76 (95% CI, 0.64–0.88) and the Clinical (and corresponding L-TRiP(ascopy)) model an AUC of 0.72 (95% CI, 0.60–0.83). In the internal and external validation, the Complete model reached an AUC of 0.78 (95% CI, 0.52–0.98) and 0.75 (95% CI, 0.42–1.00), respectively, while the other models performed slightly less well.

Het meest voorgeschreven type anticonceptiepil, Microgynon® ‘30’, was in het afgelopen najaar niet overal beschikbaar. Minister Bruins adviseerde om zolang het tekort duurde ‘even voor een andere pil te kiezen’. Dat was geen goede raad. Een ander type anticonceptiepil kan, ook bij kortdurend gebruik, een gevaarlijke bijwerking hebben: veneuze trombo-embolie.

The role of the fibrinolytic system in the development of venous thrombosis (VT) is unclear. We studied the risk of first and recurrent VT associated with reduced fibrinolysis, as measured by clot lysis time (CLT). We also studied the relationship between CLT and thrombin generation to determine if any relationship between CLT and VT was affected by thrombin generation. Analyses were performed in the Thrombophilia Hypercoagulability Environmental risk for Venous Thromboembolism Study, a two-centre population-based case-control study, including 579 patients and 338 controls, with patients followed from the event to determine incidence of recurrent VT. Hypofibrinolysis was associated with a 1·8-fold increased risk of a first VT [95% confidence interval (CI) 1·2-2·7]. Adjustment for sex, age, study location and Endogenous Thrombin Potential (ETP) did not change the result. The risk of VT was 2·9-fold increased when the 90th percentiles of prolonged CLT and high ETP were combined, with the highest risk for unprovoked first events (Odds Ratio = 4·2, 95% CI 1·3-13·5). In the follow-up study the Hazard Ratio for a recurrent VT associated with hypofibrinolysis was 1·5 (95% CI 0·9-2·6). A weak dose response effect was observed in relation to prolongation of CLT and recurrent VT. Although hypofibrinolysis constitutes a risk factor for a first VT, an association with recurrence is, at best, weak.