Per- and polyfluoroalkyl substances (PFAS) are widely used and persistent chemicals, leading to ubiquitous exposure. Although high PFAS levels have been associated with an adverse cardiovascular... Show morePer- and polyfluoroalkyl substances (PFAS) are widely used and persistent chemicals, leading to ubiquitous exposure. Although high PFAS levels have been associated with an adverse cardiovascular risk profile, the distribution of levels and relations with cardio-metabolic risk markers in the general population have not been fully characterized. We assessed the association between blood levels of perfluorooctaneic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) and a range of lipoproteins and metabolites as well as clinical lipid measurements. We used data from participants of the Netherlands Epidemiology of Obesity study (NEO) (n = 584) and the Rhineland Study (n = 1962), jointly spanning an age range of 30 to 89 years. PFAS were measured with the Metabolon HD4 platform, and lipoprotein and metabolite profiles were measured using Nightingale's nuclear magnetic resonance-spectroscopy platform, and mainly comprised lipoprotein markers. Using linear regression analyses, we quantified age-, sex-, and education-adjusted associations of PFOA, PFOS, and PFHxS with clinical lipid measurements and 224 lipoproteins and metabolites. Higher levels of PFAS, particularly PFOS and PFHxS, were associated with higher concentrations of total lipid, cholesterol and phospholipid content in most HDL, IDL, LDL, and VLDL subclasses. The effect sizes were age-dependent for the majority of the associations, with the deleterious effects of PFAS being generally stronger in people below compared to those above median age. Our observation that in the general population even low PFAS concentrations are associated with an unfavorable lipid profile, calls for further critical regulation of PFAS substances. Show less
Yuan, L.S.; Han, J.H.; Velden, A.I.M.V.; Vink, H.; Mutsert, R. de; Rosendaal, F.R.; ... ; Berg, B.M. van den 2023
Background: Microvascular dysfunction is a growing determinant of sex differences in coronary heart disease (CHD). Dysregulation of the coagulation system is involved in CHD pathogenesis and can be... Show moreBackground: Microvascular dysfunction is a growing determinant of sex differences in coronary heart disease (CHD). Dysregulation of the coagulation system is involved in CHD pathogenesis and can be induced by endothelial glycocalyx (EG) perturbation. However, little is known about the link between EG function and coagulation parameters in population-based studies on sex specificity.Objectives: We sought to examine the sex differences in the relationship between EG function and coagulation parameters in a middle-aged Dutch population.Methods: Using baseline measurements of 771 participants from the Netherlands Epidemiology of Obesity study (age, 56 years [IQR, 51-61 years]; 53% women; body mass index, 27.9 kg/m2 [IQR, 25.1-30.9 kg/m2 ]), associations between glycocalyxrelated perfused boundary region (PBR) derived using sidestream dark-field imaging and coagulation parameters (factor [F]VIII/IX/XI; thrombin generation parameters; and fibrinogen) were investigated using linear regression analyses, adjusting for possible confounders (including C-reactive protein, leptin, and glycoprotein acetyls), followed by sex-stratified analyses.Results: There was a sex difference in the associations between PBR and coagulation parameters. Particularly in women, 1-SD PBR (both total and feed vessel, indicating poorer glycocalyx status) was associated with higher FIX activity ([1.8%; 95% CI, 0.3%- 3.3%] and [2.0%; 95% CI, 0.5%-3.4%], respectively) and plasma fibrinogen levels ([5.1 mg/dL; 95% CI, 0.4-9.9 mg/dL] and [5.8 mg/dL; 95% CI, 1.1-10.6 mg/dL], respectively). Furthermore, 1-SD PBRcapillary was associated with higher FVIII activity (3.5%; 95% CI, 0.4%-6.5%) and plasma fibrinogen levels (5.3 mg/dL; 95% CI, 0.6-10.0 mg/dL).Conclusion: We revealed a sex-specific association between microcirculatory health and procoagulant status, which suggests that microvascular health be considered during early development of CHD in women. Show less
BackgroundThere is limited information on short- and long-term effects of venous thromboembolism (VTE) on health-related quality of life (HRQoL) in the elderly.ObjectivesTo assess change in generic... Show moreBackgroundThere is limited information on short- and long-term effects of venous thromboembolism (VTE) on health-related quality of life (HRQoL) in the elderly.ObjectivesTo assess change in generic HRQoL and disease-specific HRQoL in patients 1 year after the VTE.MethodsThe Age and Thrombosis, Acquired and Genetic risk factors in the elderly (AT-AGE) study is a 2-center case-control study performed in Leiden, the Netherlands, and Vermont, United States, among individuals aged ≥70 years. We measured generic HRQoL using the 36-item Short Form Health Survey (SF-36) and disease-specific HRQoL using the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms Questionnaire (VEINES-QoL/Sym) and the Pulmonary Embolism–Specific Quality of Life Questionnaire (PEmb-QoL). All patients completed these questionnaires shortly after their VTE and 1 year later, while controls completed the 36-item Short Form Health Survey questionnaire once. Linear regression for change in quality of life scores was performed and adjusted for potential confounders.ResultsFor the current analysis, we included patients who were visited twice (n = 316) and controls (n = 427) with HRQoL information. Mean age of patients and controls was similar (78.8 vs 75.5 years). In patients who survived at least 1 year after the VTE, generic HRQoL improved for both summary scores, but it did not reach the level of the age-matched controls: physical and mental summary scores increased by 5.6 and 5.5 points, respectively, but compared with controls, remained 8.2 and 6.4 points lower. For disease-specific HRQoL, the Pulmonary Embolism–Specific Quality of Life Questionnaire overall score decreased from 21.7% to 15.2%, indicating improved HRQoL. Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms Questionnaire scores did not change over time.ConclusionOverall, the quality of life of patients with VTE was worse than that of controls after 1 year, indicating a long-term impact of VTE diagnosis in the elderly. Show less
Background: There is room for improvement of prevention of venous thromboembolism (VTE) after lower-leg cast application or knee arthroscopy. Information about the mechanism of clot formation in... Show moreBackground: There is room for improvement of prevention of venous thromboembolism (VTE) after lower-leg cast application or knee arthroscopy. Information about the mechanism of clot formation in these patients may be useful to identify new prophylaxis targets. We aimed to study the effect of 1) lower-leg injury and 2) knee arthroscopy on thrombin generation. Methods: A cross-sectional study was conducted using plasma samples of POT-(K)CAST trials to measure ex vivo thrombin generation (Calibrated Automated Thrombography [CAT]) and plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT), fibrinopeptide A (FPA). Plasma was obtained shortly after lower-leg trauma or before and after (< 4 h) knee arthroscopy. Participants were randomly selected from those who did not develop VTE. For aim 1, samples of 88 patients with lower-leg injury were compared with 89 control samples (i.e., preoperative samples of arthroscopy patients). Linear regression was used to obtain mean differences (or ratios if ln-retransformed because of skewedness) adjusted for age, sex, body mass index, comorbidities. For aim 2, pre- and postoperative samples of 85 arthroscopy patients were compared, for which mean changes were obtained. Results: In patients with lower-leg injury (aim 1), endogenous thrombin potential, thrombin peak, velocity index, FPA and TAT were increased as compared with controls. In arthroscopy patients (aim 2), pre- and postoperative levels were similar for all parameters. Conclusion: Lower-leg trauma increases thrombin generation both ex vivo and in vivo, in contrast to knee arthroscopy. This may imply that the pathogenesis of VTE is different in both situations. Show less
Munsch, G.; Goumidi, L.; Vlieg, A.V.; Ibrahim-Kosta, M.; Bruzelius, M.; Deleuze, J.F.; ... ; Trégouët, D.A. 2023
BackgroundIn studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. When the studied risk factors are independent of... Show moreBackgroundIn studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. When the studied risk factors are independent of time, including both pre- and post-inclusion events in the analyses, generally referred to as relying on an ambispective design, increases the statistical power but may lead to a selection bias. In the field of venous thromboembolism (VT), ABO blood groups have been the subject of extensive research due to their substantial effect on VT risk. However, few studies have investigated their effect on the risk of VT recurrence. Motivated by the study of the association of genetically determined ABO blood groups with VT recurrence, we propose a methodology to include pre-inclusion events in the analysis of ambispective studies while avoiding the selection bias due to mortality.MethodsThis work relies on two independent cohorts of VT patients, the French MARTHA study built on an ambispective design and the Dutch MEGA study built on a standard prospective design. For the analysis of the MARTHA study, a weighted Cox model was developed where weights were defined by the inverse of the survival probability at the time of data collection about the events. Thanks to the collection of information on the vital status of patients, we could estimate the survival probabilities using a delayed-entry Cox model on the death risk. Finally, results obtained in both studies were then meta-analysed.ResultsIn the combined sample totalling 2,752 patients including 993 recurrences, the A1 blood group has an increased risk (Hazard Ratio (HR) of 1.18, p = 4.2 x 10(-3)) compared with the O1 group, homogeneously in MARTHA and in MEGA. The same trend (HR = 1.19, p = 0.06) was observed for the less frequent A2 group.ConclusionThe proposed methodology increases the power of studies relying on an ambispective design which is frequent in epidemiologic studies about recurrent events. This approach allowed to clarify the association of ABO blood groups with the risk of VT recurrence. Besides, this methodology has an immediate field of application in the context of genome wide association studies. Show less
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,... Show moreBackground 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 <6.59 x 10(-5)), including 106 endogenous, 1 xenobiotic and 11 partially characterized/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl-ceramide and lactosyl-ceramide. We also identified a novel possible HTGC-related pathway connecting glutamate, metabolonic lactone sulphate and X-15245 using the GGM network. These pathways were confirmed to be associated with the FIB-4 index as well. The full interactive metabolite-HTGC atlas is provided online: . Conclusions: The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB-4 index. Moreover, we report a novel pathway glutamate-metabolonic lactone sulphate-X-15245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis-related outcomes. Show less
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... Show moreTandem 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 (<36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable-similar to those of higher risk of coronary artery disease and type 2 diabetes-and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI. Show less
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... Show moreBackground: 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. Show less
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross... Show morePrevious genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries. Show less
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... Show moreMen 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. Show less
Wang, H.J.; Cushman, M.; Rosendaal, F.R.; Vlieg, A.V. 2022
IMPORTANCE Previous venous thrombosis (VT) is associated with risk of future VT, but quantification of risk over the life course is poorly understood. More information is needed for clinicians to... Show moreIMPORTANCE Previous venous thrombosis (VT) is associated with risk of future VT, but quantification of risk over the life course is poorly understood. More information is needed for clinicians to understand the association of remote history of VT with the risk of VT in older patients.OBJECTIVE To assess the association between a remote history of VT and the development of VT in older age.DESIGN, SETTING, AND PARTICIPANTS The Age and Thrombosis, Acquired and Genetic Risk Factors in the Elderly case-control study enrolled patients 70 years and older with VT and control individuals 70 years and older without VT between June 2008 and August 2011. The Age and Thrombosis, Acquired and Genetic Risk Factors in the Elderly study is a 2-center, population-based case-control study that was conducted in Burlington, Vermont, in the US and in Leiden, the Netherlands. Consecutively diagnosed patients with an objectively proven episode of VT (deep vein thrombosis of the leg or pulmonary embolism) were included. Control individualswere identified in the same geographic areas as the patients andwere randomly selected. Datawere analyzed between May 2021 and October 2021.EXPOSURES Self-reported remote VT (occurring >10 years before to enrollment).MAIN OUTCOMES AND MEASURES The main outcome was the risk of VT at older age. The association of self-reported history of remote VT with VT at older age was assessed by calculating odds ratios (ORs) as estimates of relative risk with 95% CIs.RESULTS A total of 460 patients with VT and 456 control participants were included. There were slightly more women than men in both groups (60.2% of patients [n = 277] were women and 52.4% of control participants [n = 239] were women), and the mean (range) age of patients was 78.7 (70.0-100.9) years, which was similar to the control participants. Compared with individuals without remote VT, those with a remote history of VT had an increased risk of VT (OR, 2.54; 95% CI, 1.56-4.13). The crude risk estimate was robust to adjustment and time since remote VT, that is, individuals with a VT 10 to 30 years ago (OR, 2.74; 95% CI, 1.34-5.57) and those with a VT more than 30 years ago (OR, 2.42; 95% CI, 1.21-4.84) had a an increased risk of VT. The populationattributable fraction of a remote history of VT was 7.7%.CONCLUSIONS AND RELEVANCE In this study, a remote history of VT was associated with risk of VT in older individuals. This quantification could assist clinicians in advising patients on VT prevention. Show less
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... Show moreIn 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. Show less
Wang, H.J.; Rosendaal, F.R.; Cushman, M.; Vlieg, A.V. 2022
Background: The preponderance of the evidence supports no association between traditional cardiovascular risk factors and venous thromboembolism (VTE), other than obesity. There are limited data in... Show moreBackground: The preponderance of the evidence supports no association between traditional cardiovascular risk factors and venous thromboembolism (VTE), other than obesity. There are limited data in older people.Objectives: To investigate whether cardiovascular risk factors (body mass index, smoking, alcohol intake, hypertension, and diabetes) are associated with the risk of VTE in elderly and to assess the combined effect between cardiovascular risk factors and genetic risk factors for VTE (factor V Leiden/prothrombin 20210A, positive family history of VTE, and non-O blood group).Methods: The Age and Thrombosis, Acquired and Genetic risk factors in the Elderly study is a multicenter case-control study performed in Vermont, USA and Leiden, the Netherlands, comprising 401 cases with first VTE and 431 control subjects, all aged >= 70 years. To assess the risk of VTE, odds ratios (OR) with 95% confidence intervals (Cis) were calculated, adjusting for potential confounders.Results: Both height and weight were positively associated with VTE risk: the ORs were 2.2 (95% CI, 1.2-3.9) and 1.5 (95% CI, 1.0-2.4) in the top quartile for height and weight separately. This risk was more pronounced for unprovoked VTE. Smoking, alcohol intake, and diabetes were not associated with VTE. Higher systolic and diastolic blood pressure and hypertension were associated with a decreased risk of VTE. In the presence of a genetic predisposition, height and weight further increased the risk of VIE.Conclusions: In the elderly, height and weight are positively associated with the risk of VTE. With genetic predisposition, higher levels of height and weight further increase the risk of VTE. Show less
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... Show moreGlycemic 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 < 5 x 10(-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. Show less
Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate... Show moreGenetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact ofABOlocus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, similar to 1.2), the A1 and B haplotypes are associated with an similar to 1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, similar to 0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits. Show less
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... Show moreBackground 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 hormone trials. Women were randomized to hormone therapy or placebo. Biomarkers were measured at baseline and after 1 year in 217 cases and 817 controls.Results Increased APC resistance and decreased TFPI at baseline were associated with VT (odds ratio 1.20-2.06). However, women with such prothrombotic profile at baseline did not have further increased risk of VT when randomized to HT compared with placebo. Although there was no change in APC resistance or TFPI in placebo group after 1 year, HT group showed prothrombotic changes in the biomarkers (i.e., an increase in APC resistance) (mean [standard deviation] 0.39 [0.54]) and decrease in TFPI (-0.21 [0.50]: free TFPI, -0.24 [0.22]: TFPI activity -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 before 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. Show less
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... Show moreBackground: 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. Show less
Wang, H.J.; Rosendaal, F.R.; Cushman, M.; Vlieg, A.V. 2020
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.... Show moreEssentials 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. Show less
Wang, H.J.; Rosendaal, F.R.; Cushman, M.; Vlieg, A.V. 2020
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... Show moreBackground: 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. Show less
Morelli, V.M.; Mutsert, R. de; Roos, A. de; Lamb, H.J.; Vlieg, A.V.; Bos, M.H.A.; ... ; Cannegieter, S.C. 2020
Objective:Whether hepatic triglyceride content (HTGC) contributes to hypercoagulability beyond total body fat (TBF) and visceral adipose tissue (VAT) is unclear. We, therefore, aimed to investigate... Show moreObjective:Whether hepatic triglyceride content (HTGC) contributes to hypercoagulability beyond total body fat (TBF) and visceral adipose tissue (VAT) is unclear. We, therefore, aimed to investigate the association between HTGC and coagulation factors (F)I (fibrinogen), VIII, IX, and XI while adjusting for TBF and VAT.Approach and Results:In this cross-sectional analysis of the NEO study (Netherlands Epidemiology of Obesity; n=6671), a random subset of participants underwent magnetic resonance imaging and magnetic resonance spectroscopy to assess VAT and HTGC (n=2580). We excluded participants without complete imaging and coagulation assessment, and with history of liver disease, venous thrombosis, or on anticoagulation. Mean differences in coagulation factor levels across HTGC quartiles were estimated by linear regression adjusted for age, sex, ethnicity, education, alcohol intake, physical activity, smoking, estrogen, and menopause, in addition to TBF and VAT. Among the 1946 participants included, median HTGC was 2.66% (interquartile range: 1.34%-6.27%). Coagulation factor levels increased dose-dependently across HTGC quartiles. Mean differences between the fourth and first quartiles were 14.7 mg/dL (95% CI, 2.1-27.2) for fibrinogen, 6.7 IU/dL (95% CI, 0.5-12.9) for FVIII, 26.1 IU/dL (95% CI, 22.4-29.8) for FIX, and 8.6 IU/dL (95% CI, 4.6-12.6) for FXI. With further adjustment for TBF and VAT, the dose-response association of HTGC with FIX persisted, whereas associations with other factors disappeared.Conclusions:HTGC was associated with various coagulation factors, of which FIX remained associated with HTGC after adjustment for TBF and VAT. HTGC might contribute to venous thrombosis risk beyond total body and visceral fat through FIX levels. Show less
