Obesity-related venous thromboembolism

Venous thromboembolism (VTE), a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common and multicausal disease. Obesity is a major and likely causal risk factor for VTE. However, to what extent obesity contributes to VTE risk in the general population and the mechanism of obesity-related VTE remain poorly understood. The overall aim of this thesis was (i) to determine the risk of VTE attributed to obesity at population level and (ii) to reveal biomarkers of obesity-related VTE. The study population in all papers was recruited from the 4th-7th surveys of the Tromsø Study (enrolment: 1994-2016), a population-based cohort study. Paper II also included participants from the Trøndelag Health Study (HUNT 2). Exposure information was obtained at survey inclusion through self-administered questionnaires, physical examination, and blood samples. Incident VTE events during follow-up were registered and objectively validated. In paper I, to assess the VTE risk attributed to overweight and obesity, we calculated the population attributable fraction (PAF) using a cohort design and repeated measurements of body mass index (BMI). The PAF of incident VTE due to overweight (BMI 25-30 kg/m2) and obesity (BMI ≥30 kg/m2) was 24.6% (12.9% was attributed to overweight and 11.7% to obesity). In paper II, the joint effect of obesity and established prothrombotic genotypes (rs8176719 in ABO, rs6025 in F5, rs1799963 in F2, rs2066865 in FGG, and rs2036914 in F11) on VTE risk was investigated. Using a case-cohort design, it was observed that the combination of obesity and prothrombotic genotypes, assessed either individually or as a genetic risk score, had an additive effect on VTE risk (i.e., no biological interaction). However, the combination of obesity and some prothrombotic genotypes appeared to have a supra-additive effect on the risk of DVT and unprovoked VTE. In papers III and IV, a nested case-control design was used to investigate whether plasma leptin and plasminogen activator inhibitor-1 (PAI-1) were associated with VTE risk and their potential to mediate the VTE risk in obesity. The VTE risk increased with increasing levels of leptin, and particularly of PAI-1. Additional adjustment for BMI markedly attenuated risk estimates for leptin, while PAI-1 remained associated with VTE. In a mediation analysis, PAI-1 mediated almost 15% of the VTE risk in obesity, while no apparent mediation was observed for leptin. In conclusion, the main findings of this thesis indicate that obesity is a major risk factor for VTE at population level and that PAI-1 levels mediate part of the VTE risk in obesity

Joint Effect of Multiple Prothrombotic Genotypes and Mean Platelet Volume on the Risk of Incident Venous Thromboembolism

Background - A high mean platelet volume (MPV), a marker of increased platelet reactivity, is a risk factor for venous thromboembolism (VTE). Whether established prothrombotic single nucleotide polymorphisms (SNPs) further increase the VTE risk in subjects with high MPV because of biological interaction remains unknown. Aim - To investigate the joint effect of high MPV and prothrombotic genotypes, comprising a 5-SNP genetic risk score (GRS), on the risk of VTE in a population-based case–cohort. Methods - Incident VTE cases (n = 653) and a subcohort (n = 1,774) were derived from the Tromsø Study (1994–2012). DNA was genotyped for rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2036914 (F11), and rs2066865 (FGG). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) were estimated according to predefined MPV-strata ( Results - The combination of high MPV and risk alleles, either as individual SNPs or the GRS, had an additive effect on VTE risk. Compared with subjects with MPV Conclusion - The combination of high MPV and prothrombotic genotypes had an additive effect on VTE risk, suggesting there is no biological interaction between these risk factors in the pathogenesis of VTE

Plasma levels of leptin and risk of future incident venous thromboembolism

Abstract Background Circulating levels of leptin, an adipocyte-derived hormone, are frequently elevated in obesity. Leptin has been reported to upregulate prothrombotic hemostatic factors in vitro and could potentially mediate venous thromboembolism (VTE) risk in obesity. However, whether leptin is associated with VTE remains uncertain. Objective This article investigates the association between plasma leptin and risk of incident VTE, and the potential of leptin to mediate VTE risk in obesity. Methods A population-based nested case–control study with 416 VTE cases and 848 age- and sex-matched controls was derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across leptin quartiles. Analyses were performed separately in men and women using sex-specific quartile cut-offs determined in controls. Results In the age-adjusted model, the VTE risk increased across leptin quartiles, particularly in men. Compared with the lowest quartile, the ORs for VTE in the highest quartile were 1.70 (95% CI 1.04–2.79) in men and 1.36 (95% CI 0.85–2.17) in women. However, with additional adjustment for body mass index (BMI), risk estimates were markedly attenuated in men (OR 1.03, 95% CI 0.55–1.93) and women (OR 0.82, 95% CI 0.45–1.48). The ORs for VTE were increased in obese men and women (BMI ≥ 30 kg/m2) and were only marginally affected after adjustment for leptin. Conclusion Our results indicate that the apparent association between plasma leptin levels and VTE risk is confounded by BMI and that leptin is not a relevant mediator for VTE risk in obesity

Elevated plasma levels of plasminogen activator inhibitor-1 are associated with risk of future incident venous thromboembolism

Background: Plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of fibrinolysis, is frequently elevated in obesity and could potentially mediate the risk of venous thromboembolism (VTE) in obese subjects. However, whether PAI-1 is associated with VTE remains uncertain. Objective: To investigate the association between plasma PAI-1 levels and risk of future incident VTE and whether PAI-1 could mediate the VTE risk in obesity. Methods: A population-based nested case-control study, comprising 383 VTE cases and 782 age- and sex-matched controls, was derived from the Tromsø Study cohort. PAI-1 antigen levels were measured in samples collected at cohort inclusion. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across PAI-1 tertiles. Results: The VTE risk increased dose-dependently across PAI-1 tertiles (P for trend <.001) in the age- and sex-adjusted model. The OR of VTE for the highest versus lowest tertile was 1.73 (95% CI 1.27–2.35), and risk estimates were only slightly attenuated with additional stepwise adjustment for body mass index (BMI; OR 1.59, 95% CI 1.16–2.17) and C-reactive protein (CRP; OR 1.54, 95% CI 1.13–2.11). Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. In obese subjects (BMI of ≥30 kg/m2 vs. 2 ), PAI-1 mediated 14.9% (95% CI 4.1%-49.4%) of the VTE risk in analysis adjusted for age, sex, and CRP. Conclusion: Our findings indicate that plasma PAI-1 is associated with increased risk of future incident VTE and has the potential to partially mediate the VTE risk in obesity

Joint Effect of Multiple Prothrombotic Genotypes and Obesity on the Risk of Incident Venous Thromboembolism

Background The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear. Objective To investigate the joint effect of obesity and a genetic risk score (GRS) composed of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case–cohort. Methods Cases with incident VTE ( n= 1,470) and a subcohort ( n = 12,826) were derived from the Tromsø Study (1994–2012) and the Trøndelag Health Study (HUNT) (1995–2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0–1, 2, 3, ≥4 alleles). Results The combination of obesity (BMI ≥ 30kg/m2) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e., no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence interval [CI]: 2.05–3.96) increased risk of overall VTE compared with those with BMI 2 and 0 to 1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR: 3.20; 95% CI: 2.09–4.90) and unprovoked VTE (HR: 3.82; 95% CI: 2.25–6.47), suggesting a supra-additive effect. Conclusion Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE

Joint Effect of Multiple Prothrombotic Genotypes and Obesity on the Risk of Incident Venous Thromboembolism

Background The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear. Objective To investigate the joint effect of obesity and a genetic risk score (GRS) composed of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case–cohort. Methods Cases with incident VTE (n = 1,470) and a subcohort (n = 12,826) were derived from the Tromsø Study (1994–2012) and the Trøndelag Health Study (HUNT) (1995–2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0–1, 2, 3, ≥4 alleles). Results The combination of obesity (BMI ≥ 30kg/m2) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e., no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence interval [CI]: 2.05–3.96) increased risk of overall VTE compared with those with BMI <25 kg/m2 and 0 to 1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR: 3.20; 95% CI: 2.09–4.90) and unprovoked VTE (HR: 3.82; 95% CI: 2.25–6.47), suggesting a supra-additive effect. Conclusion Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE