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2.
Thromb Res ; 184: 99-104, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715545

RESUMO

BACKGROUND: The effects of statins in prevention of venous thromboembolism (VTE) is not well established. OBJECTIVES: To examine the risks of first-time VTE in a cohort of patients initiating statin treatment and in a matched general population comparison cohort. METHODS: We conducted a nationwide, population-based, matched cohort study based on data from Danish health registries. The study period was 1 January 2005-31 December 2015. We identified statin initiators (without VTE, myocardial infarction, or ischemic stroke) and sex-, age-, and calendar year-matched (1,3) individuals from the general population (without statin use, VTE, myocardial infarction, or ischemic stroke). We computed cumulative risks and comorbidity-adjusted hazard ratios (HRs) of VTE, myocardial infarction, and ischemic stroke. RESULTS: Among 601,011 statin initiators and 1,803,033 matched population cohort members during 2005-2015, the cumulative risk after 11 years was 2.8% for VTE (both cohorts), 4.7% vs. 2.9% for myocardial infarction, and 7.1% vs. 5.2 for ischemic stroke. After adjustment, statin use was associated with a slightly decreased risk of VTE (adjusted HR: 0.95 [95% CI: 0.92-0.97]), driven by a reduced risk of unprovoked VTE (adjusted HR: 0.92 [95% CI: 0.89-0.95]). The reduced risks of VTE were more pronounced among patients who had an imaging examination performed. The adjusted HRs were elevated for myocardial infarction and ischemic stroke. CONCLUSION: Statin initiation was associated with a reduced risk of VTE, with no indication of a healthy-user effect. Based on available evidence, statins have weak thromboprophylactic effects.

3.
Haematologica ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582554

RESUMO

Venous thromboembolism is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of venous thromboembolism, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of venous thromboembolism. Cases with incident venous thromboembolism (n= 640) and a randomly selected age-weighted sub-cohort (n=3734) were derived from a population-based cohort (the Tromso study). Cox-regression was used to estimate hazard ratios with 95% confidence intervals for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7 95% CI 1.2-2.3) increased risk of venous thromboembolism compared to non-carriers. Cancer patients homozygous for the FGG variant had a 2-fold (HR 2.0 95% CI 1.1-3.6) higher risk of venous thromboembolism than cancer patients without the variant. Moreover, the 6-month cumulative incidence of venous thromboembolism among cancer patients was 6.4% (95% CI, 3.5%-11.6%) in homozygous carriers of FGG and 3.1% (95% CI, 2.3%-4.7%) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (Synergy index: 1.81, 95% CI: 1.02-3.21, Attributable proportion: 0.43, 95% CI: 0.11-0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded synergistic effect on the risk of venous thromboembolism.

4.
Thromb Haemost ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659738

RESUMO

BACKGROUND: Limited knowledge exists on the association between intake of long-chained n-3 polyunsaturated fatty acids (n-3 PUFAs) and risk of recurrence and all-cause mortality in patients with venous thromboembolism (VTE). OBJECTIVES: This article investigates whether intake of marine n-3 PUFAs was associated with risk of recurrence and mortality in patients with incident VTE. METHODS: A total of 595 patients with incident VTE and available data on n-3 PUFA intake were derived from the Tromsø Study surveys 4 (1994-1995) and 6 (2007-2008). Weekly intake of n-3 PUFAs was categorized as low, medium, and high based on tertiles. Recurrent VTEs and all-cause mortality were registered up to December 31, 2016. Hazard ratios (HRs) were calculated using Cox regression models with the low intake category as reference. RESULTS: There were 98 recurrent VTEs and 227 deaths during follow-up. Overall, we found no association between intake of n-3 PUFAs and risk of recurrent VTE. However, inverse associations were found for high intakes in patients with unprovoked VTE (HR 0.45, 95% confidence interval [CI]: 0.20-1.01), cancer-free patients (HR 0.51, 95% CI: 0.27-0.95), and deep vein thrombosis (DVT) patients (HR 0.49, 95% CI: 0.24-0.97). The inverse associations were more evident when follow-up was restricted to the time after discontinuation of anticoagulant therapy. No association was observed between intake of n-3 PUFAs and mortality after incident VTE. CONCLUSION: A high dietary intake of marine n-3 PUFAs was associated with lower risk of recurrent VTE after unprovoked index events, DVT, and in cancer-free patients.

5.
PLoS Med ; 16(10): e1002883, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31603898

RESUMO

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 <10%. A limitation of both cohorts is that laboratory measurements were missing in a substantial proportion of patients, which therefore were imputed. CONCLUSIONS: The prediction model we propose applies to patients with provoked or unprovoked first VTE-except for patients with (a history of) cancer-allows refined risk stratification, and is easily usable. For optimal individualized treatment, a management study in which bleeding risks are also taken into account is necessary.

6.
Blood ; 134(19): 1645-1657, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

7.
J Thromb Haemost ; 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31448518

RESUMO

BACKGROUND: Cardiorespiratory fitness (CRF) is a strong predictor of future arterial cardiovascular disease and premature mortality. However, there are limited data on the association between CRF and the risk of incident venous thromboembolism (VTE). OBJECTIVES: To investigate whether estimated CRF (eCRF) was associated with the risk of incident VTE in a cohort recruited from the general population. METHODS: Participants (n = 10 393) from the sixth survey of the Tromsø Study (2007-08) were included, and incident VTEs were recorded up to 31 December 2016. CRF was estimated in sex-specific algorithms based on age, waist circumference, resting heart rate, and self-reported physical activity. Hazard ratios (HRs) with 95% confidence intervals (CIs) of VTE according to categories of eCRF were estimated in Cox regression models adjusted for sex with age as timescale. The impact of weight status was evaluated in analyses stratified by weight category. RESULTS: There were 176 incident VTEs during follow-up. Compared with individuals with eCRF < 85% of age-predicted, those with eCRF of 85% to 100% and >100% of age-predicted had 46% (HR 0.54; 95% CI 0.39-0.77) and 67% (HR 0.33; 95% CI 0.20-0.54) lower VTE risk, respectively. Compared with overweight/obese individuals with eCRF < 85% of age-predicted, overweight/obese individuals with eCRF ≥ 85% had 50% (HR 0.50, 95% CI 0.35-0.74) lower risk, and normal weight individuals with eCRF ≥ 85% had 55% (HR 0.45, 95% CI 0.30-0.68) lower risk. CONCLUSIONS: Higher eCRF was associated with lower risk of incident VTE. The association was independent of weight categories, suggesting that higher eCRF may modify the association between obesity and VTE.

8.
Thromb Haemost ; 119(8): 1358-1364, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203579

RESUMO

Patients with myocardial infarction (MI) are at increased short-term risk of venous thromboembolism (VTE). The mechanisms behind this association are unclear. We aimed to investigate the impact of acute MI as a transient risk factor for incident VTE while taking other concomitant VTE risk factors into account. We conducted a case-crossover study of VTE patients (n = 707) recruited from the fourth survey of the Tromsø Study. VTE risk factors and hospitalizations were registered during the 90-day period preceding the VTE diagnosis (hazard period) and in four 90-day control periods. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to acute MI and after adjustment for other risk factors. Additionally, we applied a mediation analysis to quantify how much the known transient risk factors account for the observed effect of MI on VTE risk. MI was recorded in 13 (1.8%) of the hazard periods and in 6 (0.2%) of the control periods, which yielded a crude OR of 11.9 (95% CI: 3.9-36.7). Adjustment for immobilization and infection yielded an OR of 2.7 (95% CI: 0.6-11.2). The OR was attenuated to 2.6 (95% CI: 0.6-11.9) after further adjustment for major surgery, trauma, red blood cell transfusion, and central venous catheterization. Approximately 60% of the association between MI and VTE was mediated through infection and immobilization. In conclusion, our findings suggest that the increased VTE risk after MI may to a large extent be explained by concomitant conditions related to MI, particularly infections and immobilization.

9.
J Thromb Haemost ; 17(10): 1661-1669, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31220397

RESUMO

BACKGROUND: Animal and observational studies have suggested a pathophysiological role for complement in venous thromboembolism (VTE), but the initiating mechanisms are unknown. Mannose-binding lectin (MBL) bound to altered host cells leads to activation of the lectin complement pathway, and both high and low MBL levels have been implicated in the pathophysiology of cardiovascular disease. OBJECTIVES: To investigate the association between plasma MBL levels and future risk of incident VTE. METHODS: We conducted a nested case-control study in 417 VTE patients and 849 age-matched and sex-matched controls derived from the general population (Tromsø Study). Plasma MBL levels were measured using enzyme-linked immunosorbent assay. Logistic regression models were used to estimate odds ratio (OR) for VTE across quartiles of plasma MBL levels. RESULTS: Subjects with plasma MBL levels in the lowest quartile (<435 ng/mL) had a reduced OR for overall VTE (OR 0.79, 95% confidence interval [CI]: 0.56-1.10) and for DVT (OR 0.70, 95% CI: 0.47-1.04) compared to those with MBL in the highest quartile (≥2423 ng/mL) after multivariable adjustments. For VTE, DVT, and pulmonary embolism (PE) the ORs decreased substantially with decreasing time between blood sampling and VTE event. CONCLUSIONS: Our findings suggest that low plasma MBL levels are associated with reduced risk of VTE, and DVT in particular.

10.
J Thromb Haemost ; 17(8): 1363-1371, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124268

RESUMO

BACKGROUND: Family history of myocardial infarction (FHMI) is known to increase the risk of venous thromboembolism (VTE). OBJECTIVES: To investigate the effect of prothrombotic genotypes on the association between FHMI and VTE in a case-cohort recruited from a general population. METHODS: Cases with a first VTE (n = 1493) and a subcohort (n = 13 072) were sampled from the Tromsø study (1994-2012) and the Nord-Trøndelag health (HUNT) study (1995-2008). The DNA samples were genotyped for rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2066865 (FGG), and rs2036914 (F11). Participants with missing information on risk alleles (n = 175), FHMI (n = 2769), and BMI (n = 52) were excluded. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for VTE. To explore the role of prothrombotic genotypes for the association between FHMI and VTE, we (a) included the genotypes in the multivariable-adjusted models and (b) assessed the joint effects between FHMI and genotypes on VTE risk. RESULTS: The FHMI was associated with a 1.3-fold increased risk of VTE (HR 1.32, 95% CI 1.16-1.50) and 1.5-fold increased risk of unprovoked VTE (HR 1.47, 95% CI 1.22-1.78). The risk of VTE by FHMI did not alter after adjustment for the five genotypes. The combination of FHMI and the different prothrombotic genotypes did not result in an excess VTE risk (i.e. no biological interaction). CONCLUSIONS: Our findings suggest that the risk of VTE by FHMI is not explained by rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2066865 (FGG), and rs2036914 (F11). The combination of FHMI with prothrombotic genotypes had an additive effect on VTE risk.

11.
J Thromb Haemost ; 17(6): 901-911, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30985982

RESUMO

BACKGROUND: Limited data exist on the relationship between physical activity and major complications after incident venous thromboembolism (VTE). OBJECTIVES: To investigate whether physical activity was associated with risk of recurrence and mortality in patients with VTE recruited from the general population. METHODS: Patients with incident VTE (n = 786) derived from the Tromsø Study surveys 4-6 (1994-1995, 2001-2002, and 2007-2008) were included, and data on physical activity were dichotomized according to the activity level reported in the survey preceding the incident VTE (inactive: <1 hour per week, active: ≥1 hour per week). Recurrent VTE and all-cause mortality were registered up to December 31, 2015. Hazard ratios (HRs) for recurrence and all-cause mortality were calculated using Cox regression models with the inactive group as reference. RESULTS: There were 139 recurrences and 395 deaths during follow-up. Physical activity was not associated with the risk of recurrence in men (HR model 2: 1.48, 95% confidence interval [CI] 0.83-2.65) or in women (HR model 2: 0.95, 95% CI 0.52-1.74). In contrast, physical activity was associated with a 28% lower risk of mortality during 10 years of follow up (HR model 3: 0.72, 95% CI 0.57-0.91). The inverse association was stronger in patients with a first deep vein thrombosis ( HR model 2: 0.59, 95% CI 0.44-0.79) than a pulmonary embolism (HR model 3: 0.87, 95% CI 0.61-1.26). CONCLUSION: Our results suggest that habitual physical activity prior to incident VTE does not influence the risk of recurrence. In contrast, active individuals were at lower risk of mortality, particularly following deep vein thrombosis.

12.
Thromb Res ; 176: 115-119, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30822715

RESUMO

BACKGROUND: Previous studies have reported that around 50% of patients with venous thromboembolism (VTE) has undergone recent hospitalization. However, studies on the impact of hospitalization as a trigger factor for VTE are limited. OBJECTIVES: To investigate the impact of hospitalization with and without concurrent immobilization as a trigger factor for VTE. METHODS: We conducted a case-crossover study of 530 cancer-free VTE patients. Hospitalizations were registered during the 90-day period preceding the VTE diagnosis (hazard period), and in four preceding 90-day control periods. A 90-day washout period between the control- and hazard periods was implemented to avoid potential carry-over effects. Conditional logistic regression was used to calculate odds ratios (OR) of VTE according to hospitalization. RESULTS: In total, 159 (30%) of the VTE-patients had been hospitalized in the hazard period, and the OR of hospitalization was 9.4 (95% CI: 6.8-12.8). The risk increased slightly with the total number of days spent in hospital (OR per day: 1.11, 95% CI: 1.04-1.18), and with the number of hospitalizations (OR 8.9, 95% CI: 6.4-12.4 for 1 hospitalization and OR 12.3, 95% CI 6.4-23.6 for ≥2 hospitalizations). Hospitalization without immobilization was 6-times (OR: 6.3, 95% CI: 4.4-9.2) more common, whereas hospitalization with immobilization was near 20-times (OR: 19.8, 95% CI: 11.5-34.0) more common in the 90-days prior to a VTE compared to the control periods. CONCLUSIONS: Hospitalization is a major trigger factor for VTE also in the absence of immobilization. However, immobilization contributes substantially to the risk of VTE among hospitalized patients.

13.
J Thromb Haemost ; 17(6): 934-943, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30920726

RESUMO

BACKGROUND: It remains uncertain whether activation of the complement system, assessed by the soluble terminal C5b-9 complement complex (plasma TCC), is associated with future risk of incident venous thromboembolism (VTE). OBJECTIVES: To investigate the association between plasma levels of TCC and future risk of incident VTE in a nested case-control study, and to explore genetic variants associated with TCC using protein quantitative trait loci analysis of exome sequencing data. METHODS: We sampled 415 VTE cases and 848 age- and sex-matched controls from a population-based cohort, the Tromsø study. Logistic regression models were used to calculate odds ratios with 95% confidence intervals for VTE across quartiles of plasma levels of TCC. Whole exome sequencing was conducted using the Agilent SureSelect 50 Mb capture kit. RESULTS: The risk of VTE increased across increasing quartiles of plasma TCC, particularly for unprovoked VTE. Participants with TCC in the highest quartile (>1.40 complement arbitrary units/mL) had an odds ratio for unprovoked VTE of 1.74 (95% confidence interval: 1.10-2.78) compared with those with TCC in the lowest quartile (≤0.80 complement arbitrary units/mL) in analyses adjusted for age, sex, and body mass index. A substantially higher risk for VTE was observed in samples taken shortly before VTE event. We found no association between genome-wide or complement-related gene variants and plasma levels of TCC. CONCLUSIONS: We found that high levels of plasma TCC were associated with VTE risk, and unprovoked events in particular. There was no genome-wide association between gene variants and plasma levels of TCC.

14.
J Thromb Haemost ; 17(5): 749-758, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30773804

RESUMO

Essentials Prothrombotic genotypes may agument the risk of venous thromboembolism (VTE) after ischemic stroke. We studied this effect in a case-cohort study using a genetic risk score. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of VTE. The risk of VTE in stroke patients increased with an increasing number of risk alleles. SUMMARY: Background Patients with ischemic stroke have a transiently increased risk of subsequent venous thromboembolism (VTE). Prothrombotic genotypes may augment VTE risk under conditions of high thrombosis risk related to stroke. Aims To investigate the effect of prothrombotic genotypes in patients with ischemic stroke on the risk of VTE in a population-based case-cohort study. Methods Cases with incident VTE (n = 664) and a randomly selected age-weighted subcohort (n = 1817) were sampled from three surveys of the Tromsø Study (1994-2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914) single-nucleotide polymorphisms (SNPs). Cox regression models were used to calculate hazard ratios (HRs) for incident VTE according to individual SNPs and categories of risk alleles (5-SNP score; 0-1, 2, 3-4 and ≥ 5) in participants with and without ischemic stroke. Results There were 192 patients with incident stroke, of whom 43 developed VTE during a median of 15.2 years of follow-up. The risk alleles of individual SNPs augmented the elevated VTE risk brought about by ischemic stroke. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of overall VTE (HR 1.5, 95% confidence interval [CI] 1.3-1.8) and an 80% higher relative risk of provoked VTE (HR 1.8, 95% CI 1.5-2.1). Stroke patients with ≥ 5 risk alleles had a 12-fold (HR 11.7, 95% CI 4.1-33.3) higher relative risk of VTE than stroke-free participants with 0-1 risk alleles. Conclusions Prothrombotic genotypes increased the risk of VTE in stroke patients, and the risk increased with an increasing number of risk alleles.

15.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
16.
Circ Genom Precis Med ; 11(12): e002170, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30562114

RESUMO

BACKGROUND: Identifying genetic variation associated with plasma protein levels, and the mechanisms by which they act, could provide insight into alterable processes involved in regulation of protein levels. Although protein levels can be affected by genetic variants, their estimation can also be biased by missense variants in coding exons causing technical artifacts. Integrating genome sequence genotype data with mass spectrometry-based protein level estimation could reduce bias, thereby improving detection of variation that affects RNA or protein metabolism. METHODS: Here, we integrate the blood plasma protein levels of 664 proteins from 165 participants of the Tromsø Study, measured via tandem mass tag mass spectrometry, with whole-exome sequencing data to identify common and rare genetic variation associated with peptide and protein levels (protein quantitative trait loci [pQTLs]). We additionally use literature and database searches to prioritize putative functional variants for each pQTL. RESULTS: We identify 109 independent associations (36 protein and 73 peptide) and use genotype data to exclude 49 (4 protein and 45 peptide) as technical artifacts. We describe 2 particular cases of rare variation: 1 associated with the complement pathway and 1 with platelet degranulation. We identify putative functional variants and show that pQTLs act through diverse molecular mechanisms that affect both RNA and protein metabolism. CONCLUSIONS: We show that although the majority of pQTLs exert their effects by modulating RNA metabolism, many affect protein levels directly. Our work demonstrates the extent by which pQTL studies are affected by technical artifacts and highlights how prioritizing the functional variant in pQTL studies can lead to insights into the molecular steps by which a protein may be regulated.


Assuntos
Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Variação Genética , Estudos de Coortes , Éxons , Feminino , Genótipo , Humanos , Masculino , Espectrometria de Massas , Proteoma/genética , Locos de Características Quantitativas , Sequenciamento Completo do Exoma
17.
Sci Rep ; 8(1): 17216, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30464183

RESUMO

Optimal pre-analytical handling is essential for valid measurements of plasma concentration and size distribution of extracellular vesicles (EVs). We investigated the impact of plasma preparation, various anticoagulants (Citrate, EDTA, CTAD, Heparin), and fasting status on concentration and size distribution of EVs measured by Nanoparticle Tracking Analysis (NTA). Blood was drawn from 10 healthy volunteers to investigate the impact of plasma preparation and anticoagulants, and from 40 individuals from a population-based study to investigate the impact of postprandial lipidemia. Plasma concentration of EVs was measured by NTA after isolation by high-speed centrifugation, and size distribution of EVs was determined using NTA and scanning electron microscopy (SEM). Plasma concentrations and size distributions of EVs were essentially similar for the various anticoagulants. Transmission electron microscopy (TEM) confirmed the presence of EVs. TEM and SEM-analyses showed that the EVs retained spherical morphology after high-speed centrifugation. Plasma EVs were not changed in postprandial lipidemia, but the mean sizes of VLDL particles were increased and interfered with EV measurements (explained 66% of the variation in EVs-concentration in the postprandial phase). Optimization of procedures for separating VLDL particles and EVs is therefore needed before NTA-assessment of EVs can be used as biomarkers of disease.

18.
Semin Thromb Hemost ; 44(8): 765-779, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30286501

RESUMO

Venous thromboembolism (VTE) is a complex multifactorial disease that represents a growing public health concern. Identification of modifiable risk factors at the population level may provide a measure to reduce the burden of VTE. In this review, we summarize current knowledge of the role of physical activity on the risk of VTE and VTE-related complications. We also discuss methodological challenges related to research on physical activity, and put forward plausible mechanisms for an association between physical activity and VTE. Up to now, published studies have reported diverging results on the relationship between physical activity and VTE, and a complex picture has emerged. However, the available evidence appears to be balanced toward a small beneficial effect of physical activity on the risk of incident VTE, but not in a dose-dependent manner. Still, the lack of an operational definition and standardized assessment method for physical activity, as well as several sources of bias, impairs the interpretation of the available literature. Additional work is necessary to understand the role and how to apply physical activity in the VTE setting. Future research should utilize objective assessment strategies of physical activity and physical fitness, account for the fluctuating nature in habitual activity levels, and explore the role of physical activity in the areas of secondary prevention and VTE-related complications.

19.
Res Pract Thromb Haemost ; 2(1): 85-92, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30046710

RESUMO

Background: A bidirectional relation exists between acute infection and immobilization, and both are triggers for venous thromboembolism (VTE). To what extent the association between infection and VTE-risk is explained by immobilization is unknown. Aims: To investigate the impact of hospitalization with acute infection on the VTE-risk in patients with and without concomitant immobilization, and to explore the differential impact of respiratory- (RTI) and urinary- (UTI) tract infections on the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods: We conducted a case-crossover study of VTE-patients (n = 707) recruited from a general population. Hospitalizations and VTE-triggers were registered during the 90 days before a VTE (hazard period) and in four preceding 90-day control periods. Conditional logistic regression was used to estimate odds ratios (ORs) for VTE according to triggers. Results: Acute infection was registered in 267 (37.8%) of the hazard periods and in 107 (3.8%) of the control periods, corresponding to a high VTE-risk after infection (OR 24.2, 95% CI 17.2-34.0), that was attenuated to 15-fold increased after adjustment for immobilization. The risk was 20-fold increased after infection without concomitant immobilization, 73-fold increased after immobilization without infection, and 141-fold increased with the two combined. The risk of PE was apparently higher after RTIs (OR 48.3, 95% CI 19.4-120.0) than UTIs (OR 12.6, 95% CI 6.4-24.7), but diminished in sensitivity analyses excluding uncertain RTI diagnoses. Conclusions: Our findings suggest that hospitalization with infection is a strong VTE-trigger also in non-immobilized patients. Infection and immobilization had a synergistic effect on the VTE-risk.

20.
Res Pract Thromb Haemost ; 2(2): 327-333, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30046735

RESUMO

Background: Red cell distribution width (RDW) is a risk marker of venous thromboembolism (VTE), myocardial infarction (MI), stroke, and cancer. Due to interrelations between these diseases, the association between RDW and VTE may be explained by MI, stroke, or cancer. Objective: To investigate whether the effect of RDW on VTE could be explained by intermediate development of MI, stroke, or cancer. Methods: RDW was measured in 24 363 participants of the Tromsø Study in 1994-1995. Incident VTE, MI, stroke, and cancer were registered until December 31, 2010. Conventional and cause-specific Cox-regression models were used to estimate hazard ratios (HR) for VTE with 95% confidence intervals (CI) across categories of RDW. Results: There were 502 first VTEs during a median follow-up of 16 years. In conventional Cox regression analysis, RDW in the highest quartile was associated with a 71% (HR 1.71, 95% CI 1.09-2.67) and 27% (HR 1.27, 95% CI 0.88-1.85) higher risk of VTE in men and women, respectively, compared to subjects in the lowest quartiles. The risk of VTE among subjects with RDW in the highest quartile was similar for men and women of postmenopausal age. In cause-specific analysis, where each individual contributed with person-time until the first occurring event only, the risk estimates were similar to those of the conventional Cox-regression analysis. Conclusion: Our findings suggest that the association between RDW and future risk of VTE is not explained by intermediate development of MI, stroke, or cancer.

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