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Platelet factor (F)XIII-A is a major cytoplasmic protein (~3% of total) representing ~50% of total circulating FXIII. However, mobilization of FXIII-A during platelet activation is not well defined. To determine mechanisms mediating the retention versus release of platelet FXIII-A, platelets from healthy humans and mice (F13a1-/-, Fga-/-, Plg-/-, Stim1fl/fl, Pf4-Cre and respective controls) were stimulated with thrombin, convulxin+thrombin, or calcium ionophore (A23187), in the absence or presence of inhibitors of transglutaminase activity, mRNA translation, microtubule rearrangement, calpain, and Rho GTPase. Platelet releasates and pellets were separated by (ultra)centrifugation. FXIII-A was detected by immunoblotting and immunofluorescence microscopy. Even following strong dual agonist (convulxin+thrombin) stimulation of human platelets, >80% platelet FXIII-A remained associated with the platelet pellet. In contrast, essentially all tissue factor pathway inhibitor, another cytoplasmic protein in platelets, was released to the supernatant. Pellet-associated FXIII-A was not due to de novo synthesis via platelet F13A1 mRNA. The proportion of platelet FXIII-A retained by, versus released from, activated platelets was partly dependent on STIM1 signaling, microtubule rearrangement, calpain, and RhoA activation, but did not depend on the presence of fibrinogen or plasminogen. Immunofluorescence microscopy confirmed the presence of considerable FXIII-A within the activated platelets. Whereas released FXIII-A was cleaved to FXIII-A* and could be degraded by plasmin, platelet-associated FXIII-A remained uncleaved. Retention of substantial platelet-derived FXIII-A by activated platelets, and its reduced susceptibility to thrombin- and plasmin-mediated proteolysis, suggests platelet FXIII-A is a protected pool with biological role(s) that differs from plasma FXIII.
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BACKGROUND & AIMS: Plant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort. METHODS: ARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n = 7690) and replication (n = 2543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n = 1358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics. RESULTS: In ARIC discovery, a total of 837 diet-protein associations (PDI = 233; provegetarian = 182; hPDI = 406; uPDI = 16) were observed at false discovery rate (FDR) < 0.05. Of these, 453 diet-protein associations (PDI = 132; provegetarian = 104; hPDI = 208; uPDI = 9) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI = 1; provegetarian = 0; hPDI = 8; uPDI = 0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests). CONCLUSIONS: Using large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions.
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Aterosclerose , Proteínas Sanguíneas , Dieta Baseada em Plantas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aterosclerose/sangue , Aterosclerose/epidemiologia , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Estudos de Coortes , Dieta Saudável/estatística & dados numéricos , Dieta Baseada em Plantas/estatística & dados numéricos , Estudos Prospectivos , Proteômica/métodos , Fatores de RiscoRESUMO
Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.
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Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.
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Importance: Obstructive sleep apnea (OSA) is a common condition in older adult (aged >65 years) populations, but more mechanistic research is needed to individualize treatments. Previous evidence has suggested an association between OSA and posttraumatic stress disorder (PTSD) but is limited by possible selection bias. High-quality research on this association with a careful evaluation of possible confounders may yield important mechanistic insight into both conditions and improve treatment efforts. Objective: To investigate the association of current PTSD symptoms and PTSD diagnosis with OSA. Design, Setting, and Participants: This cross-sectional study of twin pairs discordant for PTSD, which allows for adjustment for familial factors, was conducted using in-laboratory polysomnography from March 20, 2017, to June 3, 2019. The study sample comprised male veteran twins recruited from the Vietnam Era Twin Registry. The data analysis was performed between June 11, 2022, and January 30, 2023. Exposure: Symptoms of PTSD in twins who served in the Vietnam War. Diagnosis of PTSD was a secondary exposure. Main Outcomes and Measures: Obstructive sleep apnea was assessed using the apnea-hypopnea index (AHI) (≥4% oxygen saturation criterion as measured by events per hour) with overnight polysomnography. Symptoms of PTSD were assessed using the PTSD Checklist (PCL) and structured clinical interview for PTSD diagnosis. Results: A total of 181 male twins (mean [SD] age, 68.4 [2.0] years) including 66 pairs discordant for PTSD symptoms and 15 pairs discordant for a current PTSD diagnosis were evaluated. In models examining the PCL and OSA within pairs and adjusted for body mass index (BMI) and other sociodemographic, cardiovascular, and psychiatric risk factors (including depression), each 15-point increase in PCL was associated with a 4.6 (95% CI, 0.1-9.1) events-per-hour higher AHI. Current PTSD diagnosis was associated with an adjusted 10.5 (95% CI, 5.7-15.3) events-per-hour higher AHI per sleep-hour. Comparable standardized estimates of the association of PTSD symptoms and BMI with AHI per SD increase (1.9 events per hour; 95% CI, 0.5-3.3 events per hour) were found. Conclusions and Relevance: This cross-sectional study found an association between PTSD and sleep-disordered breathing. The findings have important public health implications and may also enhance understanding of the many factors that potentially affect OSA pathophysiology.
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Apneia Obstrutiva do Sono , Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Masculino , Apneia Obstrutiva do Sono/epidemiologia , Estudos Transversais , Idoso , Veteranos/estatística & dados numéricos , Veteranos/psicologia , Pessoa de Meia-Idade , Guerra do Vietnã , Polissonografia , Doenças em Gêmeos/epidemiologia , GêmeosRESUMO
BACKGROUND: Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT). OBJECTIVES: To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment case-only meta-analysis of genome-wide association studies (GWAS). METHODS: Use or nonuse of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and submultiplicative/supramultiplicative gene-by-environment interactions were estimated. The SI parameters were first meta-analyzed across OC and HT studies and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a P value threshold of <5.0 × 10-8; secondary analyses were candidate-based. RESULTS: The VTE case-only OC meta-analysis included 2895 OC users and 6607 nonusers; the case-only HT meta-analysis included 2434 HT users and 12 793 nonusers. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest P value approached statistical significance: rs9386463 (P = 5.03 × 10-8). We tested associations for 138 candidate variants and identified 2 that exceeded statistical significance (0.05/138 = 3.62 × 10-4): F5 rs6025 (P = 1.87 × 10-5; SI, 1.29; previously observed) and F11 rs2036914 (P = 2.0 × 10-4; SI, 0.91; new observation). CONCLUSION: The candidate variant approach to identify submultiplictive/supramultiplicative associations between genetic variation and OC and HT use identified a new association with common genetic variation in F11, while the agnostic interrogations did not yield new discoveries.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/induzido quimicamente , Feminino , Fatores de Risco , Adulto , Interação Gene-Ambiente , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepcionais Orais Hormonais/administração & dosagem , Variação Genética , Terapia de Reposição de Estrogênios/efeitos adversosRESUMO
BACKGROUND: Posttraumatic stress disorder (PTSD) causes heightened fight-or-flight responses to traumatic memories (i.e., hyperarousal). Although hyperarousal is hypothesized to cause irregular breathing (i.e., respiratory variability), no quantitative markers of respiratory variability have been shown to correspond with PTSD symptoms in humans. OBJECTIVE: In this study, we define interpretable markers of respiration pattern variability (RPV) and investigate whether these markers respond during traumatic memories, correlate with PTSD symptoms, and differ in patients with PTSD. METHODS: We recruited 156 veterans from the Vietnam-Era Twin Registry to participate in a trauma recall protocol. From respiratory effort and electrocardiogram measurements, we extracted respiratory timings and rate using a robust quality assessment and fusion approach. We then quantified RPV using the interquartile range and compared RPV between baseline and trauma recall conditions, correlated PTSD symptoms to the difference between trauma recall and baseline RPV (i.e., ∆RPV), and compared ∆RPV between patients with PTSD and trauma-exposed controls. Leveraging a subset of 116 paired twins, we then uniquely controlled for factors shared by co-twins via within-pair analysis for further validation. RESULTS: We found RPV was increased during traumatic memories (p .001), ∆ RPV was positively correlated with PTSD symptoms (p .05), and patients with PTSD exhibited higher ∆ RPV than trauma-exposed controls (p . 05). CONCLUSIONS: This paper is the first to elucidate RPV markers that respond during traumatic memories, especially in patients with PTSD, and correlate with PTSD symptoms. SIGNIFICANCE: These findings encourage future studies outside the clinic, where interpretable markers of respiratory variability are used to track hyperarousal.
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Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Processamento de Sinais Assistido por Computador , Eletrocardiografia/métodos , Respiração , IdosoRESUMO
INTRODUCTION: The effects of smoking on lung function among post-9/11 Veterans deployed to environments with high levels of ambient particulate matter are incompletely understood. MATERIALS AND METHODS: We analyzed interim data (04/2018-03/2020) from the Veterans Affairs (VA) Cooperative Studies Program #595, "Service and Health Among Deployed Veterans". Veterans with ≥1 land-based deployments enrolled at 1 of 6 regional Veterans Affairs sites completed questionnaires and spirometry. Multivariable linear regression models assessed associations between cigarette smoking (cumulative, deployment-related and non-deployment-related) with pulmonary function. RESULTS: Among 1,836 participants (mean age 40.7 ± 9.6, 88.6% male), 44.8% (n = 822) were ever-smokers (mean age 39.5 ± 9.5; 91.2% male). Among ever-smokers, 86% (n = 710) initiated smoking before deployment, while 11% (n = 90) initiated smoking during deployment(s). Smoking intensity was 50% greater during deployment than other periods (0.75 versus 0.50 packs-per-day; P < .05), and those with multiple deployments (40.4%) were more likely to smoke during deployment relative to those with single deployments (82% versus 74%). Total cumulative pack-years (median [IQR] = 3.8 [1, 10]) was inversely associated with post-bronchodilator FEV1%-predicted (-0.82; [95% CI] = [-1.25, -0.50] %-predicted per 4 pack-years) and FEV1/FVC%-predicted (-0.54; [95% CI] = [-0.78, -0.43] %-predicted per 4 pack-years). Deployment-related pack-years demonstrated similar point estimates of associations with FEV1%-predicted (-0.61; [95% CI] = [-2.28, 1.09]) and FEV1/FVC%-predicted (-1.09; [95% CI] = [-2.52, 0.50]) as non-deployment-related pack-years (-0.83; [95% CI] = [-1.26, -0.50] for FEV1%-predicted; -0.52; [95% CI] = [-0.73, -0.36] for FEV1/FVC%-predicted). CONCLUSIONS: Although cumulative pack-years smoking was modest in this cohort, an inverse association with pulmonary function was detectable. Deployment-related pack-years had a similar association with pulmonary function compared to non-deployment-related pack-years.
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Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium GWAS meta-analyses of European- (71,771 cases and 1,059,740 controls) and African-ancestry samples (7,482 cases and 129,975 controls). We used LDpred2 and PRSCSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6,261 cases and 88,238 controls) and African-ancestry sample (1,385 cases and 12,569 controls). Multi-ancestry PRSs with weights tuned in European- and African-ancestry samples, respectively, outperformed ancestry-specific PRSs in European- (PRSCSXEUR: AUC=0.61 (0.60, 0.61), PRSCSX_combinedEUR: AUC=0.61 (0.60, 0.62)) and African-ancestry test samples (PRSCSXAFR: AUC=0.58 (0.57, 0.6), PRSCSX_combined AFR: AUC=0.59 (0.57, 0.60)). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS may be used to identify individuals at highest risk for VTE and provide guidance for the most effective treatment strategy across diverse populations.
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BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race. CONCLUSION: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.
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Trombose , Tromboembolia Venosa , Trombose Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/complicações , Pacientes Internados , Teorema de Bayes , Trombose Venosa/diagnóstico , Trombose Venosa/epidemiologia , Trombose Venosa/complicações , Trombose/etiologia , Medição de Risco/métodos , Fatores de Risco , Hospitais , Estudos RetrospectivosRESUMO
OBJECTIVES: Characterise inhalational exposures during deployment to Afghanistan and Southwest Asia and associations with postdeployment respiratory symptoms. METHODS: Participants (n=1960) in this cross-sectional study of US Veterans (Veterans Affairs Cooperative Study 'Service and Health Among Deployed Veterans') completed an interviewer-administered questionnaire regarding 32 deployment exposures, grouped a priori into six categories: burn pit smoke; other combustion sources; engine exhaust; mechanical and desert dusts; toxicants; and military job-related vapours gas, dusts or fumes (VGDF). Responses were scored ordinally (0, 1, 2) according to exposure frequency. Factor analysis supported item reduction and category consolidation yielding 28 exposure items in 5 categories. Generalised linear models with a logit link tested associations with symptoms (by respiratory health questionnaire) adjusting for other covariates. OR were scaled per 20-point score increment (normalised maximum=100). RESULTS: The cohort mean age was 40.7 years with a median deployment duration of 11.7 months. Heavy exposures to multiple inhalational exposures were commonly reported, including burn pit smoke (72.7%) and VGDF (72.0%). The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively. Burn pit smoke exposure was associated with dyspnoea (OR 1.22; 95% CI 1.06 to 1.47) and chronic bronchitis (OR 1.22; 95% CI 1.13 to 1.44). Exposure to VGDF was associated with dyspnoea (OR 1.29; 95% CI 1.14 to 1.58) and wheeze (OR 1.18; 95% CI 1.02 to 1.35). CONCLUSION: Exposures to burn pit smoke and military occupational VGDF during deployment were associated with an increased odds of chronic respiratory symptoms among US Veterans.
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Bronquite Crônica , Exposição Ocupacional , Veteranos , Humanos , Adulto , Bronquite Crônica/epidemiologia , Bronquite Crônica/etiologia , Exposição Ocupacional/efeitos adversos , Estudos Transversais , Exposição Ambiental/efeitos adversos , Fumaça , Dispneia/epidemiologia , Dispneia/etiologia , Gases/análise , PoeiraRESUMO
BACKGROUND: Individuals with posttraumatic stress disorder (PTSD) face an increased risk of cardiovascular disease, but the mechanisms linking PTSD to cardiovascular disease remain incompletely understood. We used a co-twin control study design to test the hypothesis that individuals with PTSD exhibit augmented peripheral and systemic vasoconstriction during a personalized trauma recall task. METHODS: In 179 older male twins from the Vietnam Era Twin Registry, lifetime history of PTSD and current (last month) PTSD symptoms were assessed. Participants listened to neutral and personalized trauma scripts while peripheral vascular tone (Peripheral Arterial Tone ratio) and systemic vascular tone (e.g., total vascular conductance) were measured. Linear mixed-effect models were used to assess the within-pair relationship between PTSD and vascular tone indices. RESULTS: The mean age of participants was 68 years, and 19% had a history of PTSD. For the Peripheral Arterial Tone ratio analysis, 32 twins were discordant for a history of PTSD, and 46 were discordant for current PTSD symptoms. Compared with their brothers without PTSD, during trauma recall, participants with a history of PTSD had greater increases in peripheral (ß = -1.01, 95% CI [-1.72, -0.30]) and systemic (total vascular conductance: ß = -1.12, 95% CI [-1.97, -0.27]) vasoconstriction after adjusting for cardiovascular risk factors. Associations persisted after adjusting for antidepressant medication use and heart rate and blood pressure during the tasks. Analysis of current PTSD symptom severity showed consistent results. CONCLUSIONS: PTSD is associated with exaggerated peripheral and systemic vasoconstrictor responses to traumatic stress reminders, which may contribute to elevated risk of cardiovascular disease.
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Rememoração Mental , Transtornos de Estresse Pós-Traumáticos , Vasoconstrição , Humanos , Masculino , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Vasoconstrição/fisiologia , Rememoração Mental/fisiologia , Idoso , Pessoa de Meia-Idade , Sistema de RegistrosRESUMO
BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. OBJECTIVES: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.
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Hemostáticos , Acidente Vascular Cerebral , Humanos , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/genética , Fator de von Willebrand/análise , Estudo de Associação Genômica Ampla , Proteínas do Tecido Nervoso , Receptores Imunológicos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Fibrinogênio/análise , Hemostáticos/efeitos adversos , Fatores de RiscoRESUMO
Background: Over 870 000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have occurred among Veterans Health Administration users, and 24 000 have resulted in death. We examined early outcomes of SARS-CoV-2 infection in hospitalized veterans. Methods: In an ongoing, prospective cohort study, we enrolled veterans age ≥18 tested for SARS-CoV-2 and hospitalized at 15 Department of Veterans Affairs medical centers between February 2021 and June 2022. We estimated adjusted odds ratios (aORs), adjusted incidence rate ratios (aIRRs), and adjusted hazard ratios (aHRs) for maximum illness severity within 30 days of study entry (defined using the 4-category VA Severity Index for coronavirus disease 2019 [COVID-19]), as well as length of hospitalization and rehospitalization within 60 days, in relationship with demographic characteristics, Charlson comorbidity index (CCI), COVID-19 vaccination, and calendar period of enrollment. Results: The 542 participants included 329 (61%) who completed a primary vaccine series (with or without booster; "vaccinated"), 292 (54%) enrolled as SARS-CoV-2-positive, and 503 (93%) men, with a mean age of 64.4 years. High CCI scores (≥5) occurred in 61 (44%) vaccinated and 29 (19%) unvaccinated SARS-CoV-2-positive participants. Severe illness or death occurred in 29 (21%; 6% died) vaccinated and 31 (20%; 2% died) unvaccinated SARS-CoV-2-positive participants. SARS-CoV-2-positive inpatients per unit increase in CCI had greater multivariable-adjusted odds of severe illness (aOR, 1.21; 95% CI, 1.01-1.45), more hospitalization days (aIRR, 1.06; 95% CI, 1.03-1.10), and rehospitalization (aHR, 1.07; 95% CI, 1.01-1.12). Conclusions: In a cohort of hospitalized US veterans with SARS-CoV-2 infection, those with a higher CCI had more severe COVID-19 illness, more hospital days, and rehospitalization, after adjusting for vaccination status, age, sex, and calendar period.
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Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.
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Transtorno Bipolar , Transtorno Depressivo Maior , Esquizofrenia , Tromboembolia Venosa , Masculino , Humanos , Feminino , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/genética , Transtorno Bipolar/genética , Esquizofrenia/genética , Fatores de RiscoRESUMO
Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.
Assuntos
Tromboembolia Venosa , Humanos , Biomarcadores , Ativação do Complemento , Fator H do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Fator V , Tromboembolia Venosa/genéticaRESUMO
Background: Accurate and efficient methods to identify venous thromboembolism (VTE) events in hospitalized people are needed to support large-scale studies. Validated computable phenotypes using a specific combination of discrete, searchable elements in electronic health records to identify VTE and distinguish between hospital-acquired (HA)-VTE and present-on-admission (POA)-VTE would greatly facilitate the study of VTE, obviating the need for chart review. Objectives: To develop and validate computable phenotypes for POA- and HA-VTE in adults hospitalized for medical reasons. Methods: The population included admissions to medical services from 2010 to 2019 at an academic medical center. POA-VTE was defined as VTE diagnosed within 24 hours of admission, and HA-VTE as VTE identified more than 24 hours after admission. Using discharge diagnosis codes, present-on-admission flags, imaging procedures, and medication administration records, we iteratively developed computable phenotypes for POA-VTE and HA-VTE. We assessed the performance of the phenotypes using manual chart review and survey methodology. Results: Among 62,468 admissions, 2693 had any VTE diagnosis code. Using survey methodology, 230 records were reviewed to validate the computable phenotypes. Based on the computable phenotypes, the incidence of POA-VTE was 29.4 per 1000 admissions and that of HA-VTE was 3.6 per 1000 admissions. The POA-VTE computable phenotype had positive predictive value and sensitivity of 88.8% (95% CI, 79.8%-94.0%) and 99.1% (95% CI, 94.0%- 99.8%), respectively. Corresponding values for the HA-VTE computable phenotype were 84.2% (95% CI, 60.8%-94.8%) and 72.3% (95% CI, 40.9%-90.8%). Conclusion: We developed computable phenotypes for HA-VTE and POA-VTE with adequate positive predictive value and sensitivity. This phenotype can be used in electronic health record data-based research.
RESUMO
BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.