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BACKGROUND: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort. METHODS: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data. RESULTS: Among 450â 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40â 005 (8.9%) had hypercholesterolemia; 94â 785 (21.0%) had combined hyperlipidemia; 13â 998 (3.1%) had remnant hypercholesterolemia; 110â 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia. CONCLUSIONS: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.
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Doença da Artéria Coronariana , Dislipidemias , Estudo de Associação Genômica Ampla , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Dislipidemias/genética , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/diagnóstico , Idoso , Lipídeos/sangue , Adulto , Reino Unido/epidemiologia , Apolipoproteína B-100/genética , Apolipoproteína B-100/sangue , Fenótipo , Predisposição Genética para DoençaRESUMO
BACKGROUND: Guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend a risk calculator (ASCVD risk score) to estimate 10-year risk for major adverse cardiovascular events (MACE). Because the necessary inputs are often missing, complementary approaches for opportunistic risk assessment are desirable. OBJECTIVE: To develop and test a deep-learning model (CXR CVD-Risk) that estimates 10-year risk for MACE from a routine chest radiograph (CXR) and compare its performance with that of the traditional ASCVD risk score for implications for statin eligibility. DESIGN: Risk prediction study. SETTING: Outpatients potentially eligible for primary cardiovascular prevention. PARTICIPANTS: The CXR CVD-Risk model was developed using data from a cancer screening trial. It was externally validated in 8869 outpatients with unknown ASCVD risk because of missing inputs to calculate the ASCVD risk score and in 2132 outpatients with known risk whose ASCVD risk score could be calculated. MEASUREMENTS: 10-year MACE predicted by CXR CVD-Risk versus the ASCVD risk score. RESULTS: Among 8869 outpatients with unknown ASCVD risk, those with a risk of 7.5% or higher as predicted by CXR CVD-Risk had higher 10-year risk for MACE after adjustment for risk factors (adjusted hazard ratio [HR], 1.73 [95% CI, 1.47 to 2.03]). In the additional 2132 outpatients with known ASCVD risk, CXR CVD-Risk predicted MACE beyond the traditional ASCVD risk score (adjusted HR, 1.88 [CI, 1.24 to 2.85]). LIMITATION: Retrospective study design using electronic medical records. CONCLUSION: On the basis of a single CXR, CXR CVD-Risk predicts 10-year MACE beyond the clinical standard and may help identify individuals at high risk whose ASCVD risk score cannot be calculated because of missing data. PRIMARY FUNDING SOURCE: None.
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Aterosclerose , Doenças Cardiovasculares , Aprendizado Profundo , Humanos , Fatores de Risco , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco de Doenças CardíacasRESUMO
Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model's potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.
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Doença da Artéria Coronariana , Registros Eletrônicos de Saúde , Humanos , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Registros Eletrônicos de Saúde/estatística & dados numéricos , Idoso , Medição de Risco/métodos , Fatores de Risco , Adulto , Predisposição Genética para Doença , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Reino Unido/epidemiologia , Estudos Longitudinais , Herança Multifatorial/genéticaRESUMO
Importance: Earlier identification of high coronary artery disease (CAD) risk individuals may enable more effective prevention strategies. However, existing 10-year risk frameworks are ineffective at earlier identification. Understanding the variable importance of genomic and clinical factors across life stages may significantly improve lifelong CAD event prediction. Objective: To assess the time-varying significance of genomic and clinical risk factors in CAD risk estimation across various age groups. Design Setting and Participants: A longitudinal study was performed using data from two cohort studies: the Framingham Offspring Study (FOS) with 3,588 participants aged 19-57 years and the UK Biobank (UKB) with 327,837 participants aged 40-70 years. A total of 134,765 and 3,831,734 person-time years were observed in FOS and UKB, respectively. Main Outcomes and Measures: Hazard ratios (HR) for CAD were calculated for polygenic risk scores (PRS) and clinical risk factors at each age of enrollment. The relative importance of PRS and Pooled Cohort Equations (PCE) in predicting CAD events was also evaluated by age groups. Results: The importance of CAD PRS diminished over the life course, with an HR of 3.58 (95% CI 1.39-9.19) at age 19 in FOS and an HR of 1.51 (95% CI 1.48-1.54) by age 70 in UKB. Clinical risk factors exhibited similar age-dependent trends. PRS significantly outperformed PCE in identifying subsequent CAD events in the 40-45-year age group, with 3.2-fold more appropriately identified events. The mean age of CAD events occurred 1.8 years earlier for those at high genomic risk but 9.6 years later for those at high clinical risk (p<0.001). Overall, adding PRS improved the area under the receiving operating curve of the PCE by an average of +5.1% (95% CI 4.9-5.2%) across all age groups; among individuals <55 years, PRS augmented the AUC-ROC of the PCE by 6.5% (95% CI 5.5-7.5%, p<0.001). Conclusions and Relevance: Genomic and clinical risk factors for CAD display time-varying importance across the lifespan. The study underscores the added value of CAD PRS, particularly among individuals younger than 55 years, for enhancing early risk prediction and prevention strategies.
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Mass General Brigham, an integrated healthcare system based in the Greater Boston area of Massachusetts, annually serves 1.5 million patients. We established the Mass General Brigham Biobank (MGBB), encompassing 142,238 participants, to unravel the intricate relationships among genomic profiles, environmental context, and disease manifestations within clinical practice. In this study, we highlight the impact of ancestral diversity in the MGBB by employing population genetics, geospatial assessment, and association analyses of rare and common genetic variants. The population structures captured by the genetics mirror the sequential immigration to the Greater Boston area throughout American history, highlighting communities tied to shared genetic and environmental factors. Our investigation underscores the potency of unbiased, large-scale analyses in a healthcare-affiliated biobank, elucidating the dynamic interplay across genetics, immigration, structural geospatial factors, and health outcomes in one of the earliest American sites of European colonization.
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BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. OBJECTIVES: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. METHODS: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. RESULTS: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001). CONCLUSIONS: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.
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Aterosclerose , Doenças Cardiovasculares , Humanos , Pessoa de Meia-Idade , Hematopoiese Clonal/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Fator de Processamento U2AF/genética , Hematopoese/genética , Aterosclerose/genética , MutaçãoRESUMO
Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.
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The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.
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Aneurisma da Aorta Torácica , Dissecção Aórtica , Veteranos , Humanos , Estudo de Associação Genômica Ampla , Linhagem , Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genéticaRESUMO
PURPOSE: We aimed to discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). We conducted a genome-wide association study (GWAS) in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels. METHODS: We stratified the cohort based on T2D status and conducted association analyses of TG levels for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochran's Q-test and we validated the significantly associated variants in the Mass General Brigham Biobank (MGBB). RESULTS: Among 21,176 T2D and 402,944 non-T2D samples from UKB, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2 = 98.4%; pheterogeneity = 2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: -0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene, between HLA-DQB1 and HLA-DQA2 genes. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity = 9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications. CONCLUSION: In conclusion, we identified an intergenic variant near HLA-DQB1/DQA2 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Triglicerídeos , Humanos , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Triglicerídeos/metabolismoRESUMO
BACKGROUND: When indicated, guidelines recommend measurement of lipoprotein(a) for cardiovascular risk assessment. However, temporal variability in lipoprotein(a) is not well understood, and it is unclear if repeat testing may help refine risk prediction of coronary artery disease (CAD). OBJECTIVES: The authors examined the stability of repeat lipoprotein(a) measurements and the association between instability in lipoprotein(a) molar concentration with incident CAD. METHODS: The authors assessed the correlation between baseline and first follow-up measurements of lipoprotein(a) in the UK Biobank (n = 16,017 unrelated individuals). The association between change in lipoprotein(a) molar concentration and incident CAD was assessed among 15,432 participants using Cox proportional hazards models. RESULTS: Baseline and follow-up lipoprotein(a) molar concentration were significantly correlated over a median of 4.42 years (IQR: 3.69-4.93 years; Spearman rho = 0.96; P < 0.0001). The correlation between baseline and follow-up lipoprotein(a) molar concentration were stable across time between measurements of <3 (rho = 0.96), 3-4 (rho = 0.97), 4-5 (rho = 0.96), and >5 years (rho = 0.96). Although there were negligible-to-modest associations between statin use and changes in lipoprotein(a) molar concentration, statin usage was associated with a significant increase in lipoprotein(a) among individuals with baseline levels ≥70 nmol/L. Follow-up lipoprotein(a) molar concentration was significantly associated with risk of incident CAD (HR per 120 nmol/L: 1.32 [95% CI: 1.16-1.50]; P = 0.0002). However, the delta between follow-up and baseline lipoprotein(a) molar concentration was not significantly associated with incident CAD independent of follow-up lipoprotein(a) (P = 0.98). CONCLUSIONS: These findings suggest that, in the absence of therapies substantially altering lipoprotein(a), a single accurate measurement of lipoprotein(a) molar concentration is an efficient method to inform CAD risk.
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Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Fatores de Risco de Doenças Cardíacas , Lipoproteína(a)/sangue , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/tratamento farmacológico , Estudos de Coortes , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
IMPORTANCE: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized nonatherosclerotic cause of acute myocardial infarction enriched among individuals with early-onset myocardial infarction but is of unclear etiology. OBJECTIVE: To assess which genes contribute to the development of SCAD. DESIGN, SETTING, AND PARTICIPANTS: To prioritize genes influencing risk for SCAD, whole-exome sequencing was performed among individuals with SCAD in the discovery and replication cohorts from a tertiary care hospital outpatient specialty clinic, and gene set enrichment analyses were also performed for disruptive coding variants. All patients were sequentially enrolled beginning July 2013. Aggregate prevalence of rare disruptive variants for prioritized gene sets was compared between individuals with SCAD with population-based controls comprising 46â¯468 UK Biobank participants with whole-exome sequencing. Complementary mice models were used for in vivo validation. Analysis took place between June 2020 and January 2021. MAIN OUTCOMES AND MEASURES: The frequency and identity of rare genetic variants in individuals with SCAD. RESULTS: Of 130 patients, 109 (83.8%) were female (26 of 32 [81.2%] in the discovery cohort and 83 of 98 [84.7%] in the replication cohort) with mean (SD) age at first SCAD event of 48.41 (8.76) years in the discovery cohort and 47.74 (10.09) years in the replication cohort. Across all patients with SCAD, rare disruptive variants were found within 10 collagen genes (COL3A1, COL5A1, COL4A1, COL6A1, COL5A2, COL12A1, COL4A5, COL1A1, COL1A2, and COL27A1) were 17-fold (P = 1.5 × 10-9) enriched among individuals with SCAD compared with a background of 2506 constrained genes expressed in coronary artery. Furthermore, compared with individuals from the UK Biobank, individuals with SCAD were 1.75-fold (P = .04) more likely to carry disruptive rare variants within fibrillar collagen genes. Complementary mice models haploinsufficient for Col3a1 or Col5a1, the 2 most common collagen gene variants identified in SCAD cases, demonstrated increased risk of arterial dissection and increased size of arterial diameters especially in female mice, with resulting changes in collagen fibril organization and diameter. CONCLUSIONS AND RELEVANCE: Unbiased gene discovery in patients with SCAD with independent human and murine validation highlights the role of the extracellular matrix dysfunction in SCAD.
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Anomalias dos Vasos Coronários , Doenças Vasculares , Animais , Anomalias dos Vasos Coronários/genética , Feminino , Colágenos Fibrilares , Humanos , Masculino , Camundongos , Doenças Vasculares/congênito , Doenças Vasculares/genéticaRESUMO
BACKGROUND: The interval between inpatient hospitalization for symptomatic coronary artery disease (CAD) and post-discharge office consultation is a vulnerable period for adverse events. METHODS: Content was customized on a smartphone app-based platform for hospitalized patients receiving percutaneous coronary intervention (PCI) which included education, tracking, reminders and live health coaches. We conducted a single-arm open-label pilot study of the app at two academic medical centers in a single health system, with subjects enrolled 02/2018-05/2019 and 1:3 propensity-matched historical controls from 01/2015-12/2017. To evaluate feasibility and efficacy, we assessed 30-day hospital readmission (primary), outpatient cardiovascular follow-up, and cardiac rehabilitation (CR) enrollment as recorded in the health system. Outcomes were assessed by Cox Proportional Hazards model. FINDINGS: 118 of 324 eligible (36·4%) 21-85 year-old patients who underwent PCI for symptomatic CAD who owned a smartphone or tablet enrolled. Mean age was 62.5 (9·7) years, 87 (73·7%) were male, 40 of 118 (33·9%) had type 2 diabetes mellitus, 68 (57·6%) enrolled underwent PCI for MI and 59 (50·0%) had previously known CAD; demographics were similar among matched historical controls. No significant difference existed in all-cause readmission within 30 days (8·5% app vs 9·6% control, ARR -1.1% absolute difference, 95% CI -7·1-4·8, p = 0·699) or 90 days (16·1% app vs 19·5% control, p = 0.394). Rates of both 90-day CR enrollment (HR 1·99, 95% CI 1·30-3·06) and 1-month cardiovascular follow up (HR 1·83, 95% CI 1·43-2·34) were greater with the app. Weekly engagement at 30- and 90-days, as measured by percentage of weeks with at least one day of completion of tasks, was mean (SD) 73·5% (33·9%) and 63·5% (40·3%). Spearman correlation analyses indicated similar engagement across age, sex, and cardiovascular risk factors. INTERPRETATIONS: A post-PCI smartphone app with live health coaches yielded similarly high engagement across demographics and safely increased attendance in cardiac rehabilitation. Larger prospective randomized controlled trials are necessary to test whether this app improves cardiovascular outcomes following PCI. FUNDING: National Institutes of Health, Boston Scientific. CLINICAL TRIAL REGISTRATION: NCT03416920 (https://clinicaltrials.gov/ct2/show/NCT03416920).
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Doença da Artéria Coronariana/terapia , Tutoria/métodos , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aplicativos Móveis , Alta do Paciente , Projetos Piloto , SmartphoneRESUMO
Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.
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Hematopoiese Clonal/genética , Hematopoiese Clonal/fisiologia , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/citologia , Contagem de Células Sanguíneas , Aberrações Cromossômicas , Neoplasias Hematológicas/genética , HumanosRESUMO
Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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Envelhecimento/genética , Doenças Transmissíveis/genética , Pneumonia/genética , Sepse/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Bancos de Espécimes Biológicos , Aberrações Cromossômicas , Doenças Transmissíveis/complicações , Doenças Transmissíveis/microbiologia , Doenças do Sistema Digestório/epidemiologia , Doenças do Sistema Digestório/genética , Doenças do Sistema Digestório/microbiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Pneumonia/epidemiologia , Pneumonia/microbiologia , Fatores de Risco , Sepse/epidemiologia , Sepse/microbiologia , Anormalidades Urogenitais/epidemiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/microbiologia , Adulto JovemRESUMO
Krüppel-like factors (KLF) are a subfamily of the zinc-finger class of transcriptional regulators that play important roles in diverse cellular processes. While a number of KLFs are expressed in cardiomyocytes, little is known about their specific roles in the heart in vivo. Here, we demonstrate that KLF4 is induced by hypertrophic stimuli in cultured cardiomyocytes and in the mouse heart. Overexpression of KLF4 in neonatal rat ventricular myocytes inhibits three cardinal features of cardiomyocyte hypertrophy: fetal gene expression, protein synthesis, and cell enlargement. Conversely, mice with cardiomyocyte-specific deletion of KLF4 (CM-K4KO) are highly sensitized to transverse aortic constriction (TAC) and exhibit high rates of mortality. CM-K4KO mice that survive TAC display severe pathologic cardiac hypertrophy characterized by increased cardiac mass, depressed LV systolic function, pulmonary congestion, cavity dilation and attenuated LV wall thickening when compared to control genotypes. In addition, CM-K4KO mice develop increased myocardial fibrosis and apoptotic cell death after TAC. Collectively, these studies implicate KLF4 as a novel transcriptional regulator that is indispensible for the heart's response to stress in vivo.
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Cardiomegalia/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Pressão , Animais , Cardiomegalia/complicações , Células Cultivadas , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/deficiência , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Especificidade de Órgãos , RatosRESUMO
Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood1,2. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality3-11. Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.
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Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood1,2. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality3-11. Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.
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BACKGROUND: There are few published studies of the use of portable or handheld computers in health care, but these devices have the potential to transform multiple aspects of clinical teaching and practice. OBJECTIVE: This article assesses resident physicians' perceptions and experiences with tablet computers before and after the introduction of these devices. METHODS: We surveyed 49 resident physicians from 8 neurology, surgery, and internal medicine clinical services before and after the introduction of tablet computers at a 415-bed Boston teaching hospital. The surveys queried respondents about their assessment of tablet computers, including the perceived impact of tablets on clinical tasks, job satisfaction, time spent at work, and quality of patient care. RESULTS: Respondents reported that it was easier (73%) and faster (70%) to use a tablet computer than to search for an available desktop. Tablets were useful for reviewing data, writing notes, and entering orders. Respondents indicated that tablet computers increased their job satisfaction (84%), reduced the amount of time spent in the hospital (51%), and improved the quality of care (65%). CONCLUSION: The introduction of tablet computers enhanced resident physicians' perceptions of efficiency, effectiveness, and job satisfaction. Investments in this technology are warranted.
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Computadores de Mão , Internato e Residência , Satisfação no Emprego , Médicos/psicologia , Qualidade da Assistência à Saúde , Feminino , Humanos , Masculino , Inquéritos e Questionários , Fatores de TempoRESUMO
The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4's effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury.