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Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
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Diabetes Mellitus Tipo 2 , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Adipocitos/metabolismo , Cromatina/genética , Cromatina/metabolismo , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/clasificación , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/genética , Células Endoteliales/metabolismo , Células Enteroendocrinas , Epigenómica , Predisposición Genética a la Enfermedad/genética , Islotes Pancreáticos/metabolismo , Herencia Multifactorial/genética , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/genética , Análisis de la Célula IndividualRESUMEN
Distilling biologically meaningful information from cancer genome sequencing data requires comprehensive identification of somatic alterations using rigorous computational methods. As the amount and complexity of sequencing data have increased, so has the number of tools for analysing them. Here, we describe the main steps involved in the bioinformatic analysis of cancer genomes, review key algorithmic developments and highlight popular tools and emerging technologies. These tools include those that identify point mutations, copy number alterations, structural variations and mutational signatures in cancer genomes. We also discuss issues in experimental design, the strengths and limitations of sequencing modalities and methodological challenges for the future.
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Neoplasias , Mapeo Cromosómico , Biología Computacional , Variaciones en el Número de Copia de ADN , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Neoplasias/genéticaRESUMEN
Interaction analysis is a critical component of clinical and public health research and represents a key topic in precision health and medicine. In applied settings, however, interaction assessment is usually limited to the test of a product term in a regression model and to the presentation of results stratified by levels of additional covariates. Stratification of results often relies on categorizing or making linearity assumptions for continuous covariates, with substantial loss of precision and of relevant information. In time-to-event analysis, moreover, interaction assessment is often limited to the multiplicative hazard scale by inclusion of a product term in a Cox regression model, disregarding the clinically relevant information that is captured by the absolute risk scale. In this paper we present a user-friendly procedure, based on the prediction of individual absolute risks from the Cox model, for the estimation and presentation of interactive effects on both the multiplicative and additive scales in survival analysis. We describe how to flexibly incorporate interactions with continuous covariates, which potentially operate in a nonlinear fashion, provide software for replicating our procedure, and discuss different approaches to deriving CIs. The presented approach will allow clinical and public health researchers to assess complex relationships between multiple covariates as they relate to a clinical endpoint, and to provide a more intuitive and precise depiction of the results in applied research papers focusing on interaction and effect stratification.
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Modelos de Riesgos Proporcionales , Humanos , Dinámicas no Lineales , Análisis de Supervivencia , Medición de Riesgo/métodosRESUMEN
AIMS: To develop a clinical risk model to identify individuals at higher risk of developing new-onset diabetes and who might benefit more from weight loss pharmacotherapy. MATERIALS AND METHODS: A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new-onset diabetes. Twenty-seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new-onset diabetes. RESULTS: During a median (interquartile range) follow-up of 2.3 (1.8-2.7) years, new-onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high-density lipoprotein). The clinical risk model showed good discrimination (Harrell's C-indices 0.802, 95% confidence interval [CI] 0.788-0.817 and 0.807, 95% CI 0.788-0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5-year area under the curve was 81.2 [79.1-83.5]). While hazard ratios for new-onset diabetes with a weight-loss therapy were comparable across risk groups (annual risks of <1%, 1%-5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027). CONCLUSIONS: The developed clinical risk model effectively predicts new-onset diabetes, with potential implications for personalized patient care and therapeutic decision making.
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BACKGROUND: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk. METHODS: We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab. RESULTS: In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50-1.00; P=0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57-1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33-0.88]; P=0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53-0.90]; P=0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30-0.89]; P=0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk (Pinteraction 0.087 for HR; Pheterogeneity 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (Pinteraction=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (Pinteraction=0.04) and absolute VTE reduction (Pheterogeneity=0.009) in comparison with those without high genetic risk. CONCLUSIONS: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Dislipidemias/tratamiento farmacológico , Lipoproteína(a)/sangre , Inhibidores de PCSK9 , Inhibidores de Serina Proteinasa/uso terapéutico , Tromboembolia Venosa/prevención & control , Trombosis de la Vena/prevención & control , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Ensayos Clínicos como Asunto , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiología , Embolia Pulmonar/prevención & control , Medición de Riesgo , Factores de Riesgo , Inhibidores de Serina Proteinasa/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/epidemiologíaRESUMEN
BACKGROUND: The initial wave of the Covid-19 pandemic has hit Italy, and Lombardy in particular, with violence, forcing to reshape all hospitals' activities; this happened even in pediatric hospitals, although the young population seemed initially spared from the disease. "Vittore Buzzi" Children's Hospital, which is a pediatric/maternal hospital located in Milan (Lombardy Region), had to stop elective procedures-with the exception of urgent/emergent ones-between February and May 2020 to leave space and resources to adults' care. We describe the challenges of reshaping the hospital's identity and structure, and restarting pediatric surgery and anesthesia, from May on, in the most hit area of the world, with the purpose to avoid and contain infections. Both patients and caregivers admitted to hospital have been tested for Sars-CoV-2 in every case. METHODS: Observational cohort study via review of clinical charts of patients undergoing surgery between 16th May and 30th September 2020, together with SARS-CoV -2 RT-PCR testing outcomes, and comparison to same period surgeries in 2019. RESULTS: An increase of approximately 70% in pediatric surgeries (OR 1.68 [1.33-2.13], P < .001) and a higher increase in the number of surgeries were reported (OR 1.75 (1.43-2.15), P < .001). Considering only urgent procedures, a significant difference in the distribution of the type of surgery was observed (Chi-squared P-value < .001). Sars-CoV-2-positive patients have been 0.8% of total number; 14% of these was discovered through caregiver's positivity. CONCLUSION: We describe our pathway for safe pediatric surgery and anesthesia and the importance of testing both patient and caregiver.
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Servicio de Anestesia en Hospital/organización & administración , Citas y Horarios , Prueba de Ácido Nucleico para COVID-19 , COVID-19/epidemiología , Hospitales Pediátricos/organización & administración , Hospitales Universitarios/organización & administración , Pandemias , SARS-CoV-2 , Servicio de Cirugía en Hospital/organización & administración , Procedimientos Quirúrgicos Operativos/estadística & datos numéricos , Centros de Atención Terciaria/organización & administración , Adolescente , Prueba de Ácido Nucleico para COVID-19/estadística & datos numéricos , Cuidadores , Niño , Preescolar , Estudios de Cohortes , Grupos Diagnósticos Relacionados , Procedimientos Quirúrgicos Electivos/estadística & datos numéricos , Urgencias Médicas/epidemiología , Femenino , Capacidad de Camas en Hospitales/estadística & datos numéricos , Hospitales Pediátricos/estadística & datos numéricos , Hospitales Universitarios/estadística & datos numéricos , Hospitales Urbanos/organización & administración , Hospitales Urbanos/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Control de Infecciones/métodos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Italia/epidemiología , Masculino , Nasofaringe/virología , Pacientes , SARS-CoV-2/aislamiento & purificación , Evaluación de Síntomas , Centros de Atención Terciaria/estadística & datos numéricos , Adulto JovenRESUMEN
MOTIVATION: Very low-depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterization of the genotype quality and association power for very low-depth sequencing designs is still lacking. RESULTS: We perform cohort-wide whole-genome sequencing (WGS) at low depth in 1239 individuals (990 at 1× depth and 249 at 4× depth) from an isolated population, and establish a robust pipeline for calling and imputing very low-depth WGS genotypes from standard bioinformatics tools. Using genotyping chip, whole-exome sequencing (75× depth) and high-depth (22×) WGS data in the same samples, we examine in detail the sensitivity of this approach, and show that imputed 1× WGS recapitulates 95.2% of variants found by imputed GWAS with an average minor allele concordance of 97% for common and low-frequency variants. In our study, 1× further allowed the discovery of 140 844 true low-frequency variants with 73% genotype concordance when compared to high-depth WGS data. Finally, using association results for 57 quantitative traits, we show that very low-depth WGS is an efficient alternative to imputed GWAS chip designs, allowing the discovery of up to twice as many true association signals than the classical imputed GWAS design. AVAILABILITY AND IMPLEMENTATION: The HELIC genotype and WGS datasets have been deposited to the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home): EGAD00010000518; EGAD00010000522; EGAD00010000610; EGAD00001001636, EGAD00001001637. The peakplotter software is available at https://github.com/wtsi-team144/peakplotter, the transformPhenotype app can be downloaded at https://github.com/wtsi-team144/transformPhenotype. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Genotipo , Humanos , Herencia Multifactorial , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: The landscape of cancer-predisposing genes has been extensively investigated in the last 30 years with various methodologies ranging from candidate gene to genome-wide association studies. However, sequencing data are still poorly exploited in cancer predisposition studies due to the lack of statistical power when comparing millions of variants at once. METHOD: To overcome these power limitations, we propose a knowledge-based framework founded on the characteristics of known cancer-predisposing variants and genes. Under our framework, we took advantage of a combination of previously generated datasets of sequencing experiments to identify novel breast cancer-predisposing variants, comparing the normal genomes of 673 breast cancer patients of European origin against 27,173 controls matched by ethnicity. RESULTS: We detected several expected variants on known breast cancer-predisposing genes, like BRCA1 and BRCA2, and 11 variants on genes associated with other cancer types, like RET and AKT1. Furthermore, we detected 183 variants that overlap with somatic mutations in cancer and 41 variants associated with 38 possible loss-of-function genes, including PIK3CB and KMT2C. Finally, we found a set of 19 variants that are potentially pathogenic, negatively correlate with age at onset, and have never been associated with breast cancer. CONCLUSIONS: In this study, we demonstrate the usefulness of a genomic-driven approach nested in a classic case-control study to prioritize cancer-predisposing variants. In addition, we provide a resource containing variants that may affect susceptibility to breast cancer.
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Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Factores de Edad , Alelos , Biomarcadores de Tumor , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Epistasis Genética , Femenino , Frecuencia de los Genes , Genes BRCA1 , Genes BRCA2 , Genotipo , Mutación de Línea Germinal , Humanos , Masculino , Herencia Multifactorial , Mutación , Flujo de TrabajoRESUMEN
The analyses carried out using 2 different bioinformatics pipelines (SomaticSniper and MuTect) on the same set of genomic data from 133 acute myeloid leukemia (AML) patients, sequenced inside the Cancer Genome Atlas project, gave discrepant results. We subsequently tested these 2 variant-calling pipelines on 20 leukemia samples from our series (19 primary AMLs and 1 secondary AML). By validating many of the predicted somatic variants (variant allele frequencies ranging from 100% to 5%), we observed significantly different calling efficiencies. In particular, despite relatively high specificity, sensitivity was poor in both pipelines resulting in a high rate of false negatives. Our findings raise the possibility that landscapes of AML genomes might be more complex than previously reported and characterized by the presence of hundreds of genes mutated at low variant allele frequency, suggesting that the application of genome sequencing to the clinic requires a careful and critical evaluation. We think that improvements in technology and workflow standardization, through the generation of clear experimental and bioinformatics guidelines, are fundamental to translate the use of next-generation sequencing from research to the clinic and to transform genomic information into better diagnosis and outcomes for the patient.
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Bases de Datos de Ácidos Nucleicos , Frecuencia de los Genes , Genoma Humano , Leucemia Mieloide Aguda/genética , Mutación , Biología Computacional/métodos , Análisis Mutacional de ADN/métodos , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , HumanosRESUMEN
BACKGROUND: The increasing availability of resequencing data has led to a better understanding of the most important genes in cancer development. Nevertheless, the mutational landscape of many tumor types is heterogeneous and encompasses a long tail of potential driver genes that are systematically excluded by currently available methods due to the low frequency of their mutations. We developed LowMACA (Low frequency Mutations Analysis via Consensus Alignment), a method that combines the mutations of various proteins sharing the same functional domains to identify conserved residues that harbor clustered mutations in multiple sequence alignments. LowMACA is designed to visualize and statistically assess potential driver genes through the identification of their mutational hotspots. RESULTS: We analyzed the Ras superfamily exploiting the known driver mutations of the trio K-N-HRAS, identifying new putative driver mutations and genes belonging to less known members of the Rho, Rab and Rheb subfamilies. Furthermore, we applied the same concept to a list of known and candidate driver genes, and observed that low confidence genes show similar patterns of mutation compared to high confidence genes of the same protein family. CONCLUSIONS: LowMACA is a software for the identification of gain-of-function mutations in putative oncogenic families, increasing the amount of information on functional domains and their possible role in cancer. In this context LowMACA emphasizes the role of genes mutated at low frequency otherwise undetectable by classical single gene analysis. LowMACA is an R package available at http://www.bioconductor.org/packages/release/bioc/html/LowMACA.html. It is also available as a GUI standalone downloadable at: https://cgsb.genomics.iit.it/wiki/projects/LowMACA.
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Análisis Mutacional de ADN/métodos , Mutación/genética , Neoplasias/genética , Neoplasias/metabolismo , Proteínas/metabolismo , Análisis de Secuencia de Proteína/métodos , Programas Informáticos , Humanos , Proteínas/genéticaRESUMEN
MOTIVATION: Cellular mRNA levels originate from the combined action of multiple regulatory processes, which can be recapitulated by the rates of pre-mRNA synthesis, pre-mRNA processing and mRNA degradation. Recent experimental and computational advances set the basis to study these intertwined levels of regulation. Nevertheless, software for the comprehensive quantification of RNA dynamics is still lacking. RESULTS: INSPEcT is an R package for the integrative analysis of RNA- and 4sU-seq data to study the dynamics of transcriptional regulation. INSPEcT provides gene-level quantification of these rates, and a modeling framework to identify which of these regulatory processes are most likely to explain the observed mRNA and pre-mRNA concentrations. Software performance is tested on a synthetic dataset, instrumental to guide the choice of the modeling parameters and the experimental design. AVAILABILITY AND IMPLEMENTATION: INSPEcT is submitted to Bioconductor and is currently available as Supplementary Additional File S1. CONTACT: mattia.pelizzola@iit.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Precursores del ARN/genética , Estabilidad del ARN/genética , ARN Mensajero/metabolismo , ARN/genética , Análisis de Secuencia de ARN/métodos , Programas Informáticos , Algoritmos , Animales , Células Cultivadas , Regulación de la Expresión Génica , Ratones , ARN Mensajero/química , ARN Mensajero/genética , Transcripción GenéticaRESUMEN
Importance: Elevated lipoprotein(a) (Lp[a]) is a putative causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are conflicting data as to whether Lp(a) may increase cardiovascular risk only in the presence of concomitant inflammation. Objective: To investigate whether Lp(a) is associated with cardiovascular risk independent of high-sensitivity C-reactive protein (hs-CRP) in both primary and secondary prevention populations. Design, Setting, and Participants: This cohort study uses data from 3 distinct cohorts, 1 population-based cohort and 2 randomized clinical trials. Participants included individuals from the UK Biobank (data from 2006-2010) without prevalent ASCVD, participants in the FOURIER (TIMI 59) trial (data from 2013-2017) who had baseline Lp(a) and hs-CRP data, and participants in the SAVOR-TIMI 53 trial (data from 2010-2013) who had prevalent ASCVD and baseline values for Lp(a) and hs-CRP. The data analysis took place from November 2022 to November 2023. Exposure: Baseline plasma Lp(a), considered either as a continuous variable or dichotomized at 125 nmol/L. Main Outcomes and Measures: Risk of major adverse cardiovascular events (MACE) (composite of cardiovascular death, myocardial infarction [MI], or ischemic stroke), the individual MACE components, and peripheral artery disease (PAD). Results: Among 357â¯220 individuals in the UK Biobank without prevalent ASCVD, 232â¯699 (65%) had low hs-CRP (<2 mg/L), and 124â¯521 (35%) had high hs-CRP (≥2 mg/L) values. In a Cox proportional hazard model adjusted for ASCVD risk factors, higher Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP value for MACE (hs-CRP ≥2 mg/L: hazard ratio [HR] per 50-nmol/L higher Lp[a], 1.05; 95% CI, 1.04-1.07; P < .001; for hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.04-1.07; P < .001; P = .80 for interaction), as well as MI, ischemic stroke, and PAD individually. Among 34â¯020 individuals in the FOURIER and SAVOR trials with baseline cardiometabolic disease, there were 17â¯643 (52%) with low and 16â¯377 (48%) with high baseline hs-CRP values. In Cox proportional hazard models using aggregated data from FOURIER and SAVOR, higher baseline Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP for MACE (hs-CRP ≥2 mg/L: HR per 50-nmol/L higher Lp[a], 1.02; 95% CI, 1.00-1.05; P = .04; hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.02-1.08; P < .001; P = .16 for interaction), MI, and PAD. Conclusions and Relevance: In this study, higher levels of Lp(a) were associated with MACE, MI, and PAD in both primary and secondary prevention populations regardless of baseline hs-CRP value.
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Proteína C-Reactiva , Enfermedades Cardiovasculares , Lipoproteína(a) , Humanos , Aterosclerosis/epidemiología , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/epidemiología , Estudios de Cohortes , Factores de Riesgo de Enfermedad Cardiaca , Accidente Cerebrovascular Isquémico , Lipoproteína(a)/sangre , Infarto del Miocardio/epidemiología , Infarto del Miocardio/prevención & control , Factores de Riesgo , Prevención SecundariaRESUMEN
Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidized human renal and mammary epithelial cells. Proliferation-based karyotype selection in these epithelial lines modeled tissue-specific tumor aneuploidy patterns in patient cohorts in the absence of driver mutations. Hi-C-based translocation mapping revealed that arm-level events usually emerged in multiples of two via centromeric translocations and occurred more frequently in tetraploids than diploids, contributing to the increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled elucidation of pro-tumorigenic mechanisms associated with common copy number alterations, revealing Notch signaling potentiation as a driver of 1q gain in breast cancer. We propose that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.
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Aneuploidia , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Variaciones en el Número de Copia de ADN , Neoplasias/genética , Neoplasias/patología , Translocación Genética , Evolución Molecular , Proliferación Celular/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Especificidad de Órganos/genética , Células Epiteliales/metabolismo , Células Epiteliales/patologíaRESUMEN
BACKGROUND: Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. RESULTS: 21â 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. CONCLUSIONS: In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.
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Anticoagulantes , Fibrilación Atrial , Inhibidores del Factor Xa , Hemorragia , Piridinas , Tiazoles , Warfarina , Humanos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/mortalidad , Fibrilación Atrial/complicaciones , Warfarina/efectos adversos , Warfarina/administración & dosificación , Piridinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/administración & dosificación , Método Doble Ciego , Femenino , Masculino , Resultado del Tratamiento , Anciano , Hemorragia/inducido químicamente , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Factores de Tiempo , Factores de Riesgo , Persona de Mediana Edad , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/mortalidad , Anciano de 80 o más Años , Medición de RiesgoRESUMEN
Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99-1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05-1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79-1.13), Pint = 0.008), as compared to CHIP- patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.
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Importance: Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown. Objective: To develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors. Design, Setting, and Participants: This was a longitudinal cohort study using data from the Million Veteran Program (MVP; 2011-2020), UK Biobank (2006-2010), and 6 Thrombolysis in Myocardial Infarction (TIMI) trials, including DECLARE-TIMI 58 (2013-2018), FOURIER (TIMI 59; 2013-2017), PEGASUS-TIMI 54 (2010-2014), SAVOR-TIMI 53 (2010-2013), SOLID-TIMI 52 (2009-2014), and ENGAGE AF-TIMI 48 (2008-2013), which were a mix of population-based and randomized clinical trials. Individuals from UK Biobank and the MVP meeting a previously validated case/control definition for aortic stenosis were included. All individuals from TIMI trials were included unless they had a documented preexisting aortic valve replacement. Analysis took place from January 2022 to December 2023. Exposures: PRS for aortic stenosis (developed using data from MVP and validated in UK Biobank) and other previously validated cardiovascular PRSs, defined either as a continuous variable or as low (bottom 20%), intermediate, and high (top 20%), and clinical risk factors. Main Outcomes: Aortic stenosis (defined using International Classification of Diseases or Current Procedural Terminology codes in UK Biobank and MVP or safety event data in the TIMI trials). Results: The median (IQR) age in MVP was 67 (57-73) years, and 135â¯140 of 147â¯104 participants (92%) were male. The median (IQR) age in the TIMI trials was 66 (54-78) years, and 45â¯524 of 59â¯866 participants (71%) were male. The best aortic stenosis PRS incorporated 5â¯170â¯041 single-nucleotide variants and was associated with aortic stenosis in both the MVP testing sample (odds ratio, 1.41; 95% CI, 1.37-1.45 per 1 SD PRS; P = 4.6 × 10-116) and TIMI trials (hazard ratio, 1.44; 95% CI, 1.27-1.62 per 1 SD PRS; P = 3.2 × 10-9). Among genetic and clinical risk factors, the aortic stenosis PRS performed comparably to most risk factors besides age, and within a given age range, the combination of clinical and genetic risk factors was additive, providing a 3- to 4-fold increased gradient of risk of aortic stenosis. However, the addition of the aortic stenosis PRS to a model including clinical risk factors only improved risk discrimination of aortic stenosis by 0.01 to 0.02 (C index in MVP: 0.78 with clinical risk factors, 0.79 with risk factors and aortic stenosis PRS; C index in TIMI: 0.71 with clinical risk factors, 0.73 with risk factors and aortic stenosis PRS). Conclusions: This study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.
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Estenosis de la Válvula Aórtica , Infarto del Miocardio , Humanos , Masculino , Anciano , Femenino , Puntuación de Riesgo Genético , Estudios Longitudinales , Predisposición Genética a la Enfermedad , Factores de Riesgo , Estenosis de la Válvula Aórtica/genéticaRESUMEN
Importance: The clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established. Objective: To investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk. Design, Setting, and Participants: This was a longitudinal cohort study with enrollment starting on January 1, 2006, and ending on December 31, 2010, with data updated to mid-2021, using data from the UK Biobank, a long-term population study of UK citizens. A replication analysis was performed in Biobank Japan. The analysis included all patients without a history of CAD and who were not taking lipid-lowering therapy. Data were analyzed from January 1 to June 30, 2022. Exposures: Polygenic risk for CAD was defined as low (bottom 20%), intermediate, and high (top 20%) using a CAD PRS including 241 genome-wide significant single-nucleotide variations (SNVs). The pooled cohort equations were used to estimate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and classify individuals as low (<5%), borderline (5-<7.5%), intermediate (7.5-<20%), or high risk (≥20%). Main Outcomes and Measures: Myocardial infarction (MI) and ASCVD events (defined as incident clinical CAD [including MI], stroke, or CV death). Results: A total of 330â¯201 patients (median [IQR] age, 57 [40-74] years; 189â¯107 female individuals [57%]) were included from the UK Biobank. Over the 10-year follow-up, 4454 individuals had an MI. The CAD PRS was significantly associated with the risk of MI in all age groups but had significantly stronger risk prediction at younger ages (age <50 years: hazard ratio [HR] per 1 SD of PRS, 1.72; 95% CI, 1.56-1.89; age 50-60 years: HR, 1.46; 95% CI, 1.38-1.53; age >60 years: HR, 1.42; 95% CI, 1.37-1.48; P for interaction <.001). In patients younger than 50 years, those with high PRS had a 3- to 4-fold increased associated risk of MI compared with those in the low PRS category. A significant interaction between CAD PRS and age was replicated in Biobank Japan. When CAD PRS testing was added to the clinical ASCVD risk score in individuals younger than 50 years, 591 of 4373 patients (20%) with borderline risk were risk stratified into intermediate risk, warranting initiation of statin therapy and 3198 of 7477 patients (20%) with both borderline or intermediate risk were stratified as low risk, thus not warranting therapy. Conclusions and Relevance: Results of this cohort study suggest that the predictive ability of a CAD PRS was greater in younger individuals and can be used to better identify patients with borderline and intermediate clinical risk who should initiate statin therapy.
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Aterosclerosis , Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Infarto del Miocardio , Humanos , Femenino , Adulto Joven , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Estudios de Cohortes , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios Longitudinales , Medición de Riesgo/métodos , Factores de Riesgo , Infarto del Miocardio/epidemiología , Infarto del Miocardio/genética , Infarto del Miocardio/prevención & control , Aterosclerosis/tratamiento farmacológico , Prevención PrimariaRESUMEN
Pulmonary gas exchange during diving or in a dry hyperbaric environment is affected by increased breathing gas density and possibly water immersion. During free diving, there is also the effect of apnea. Few studies have published blood gas data in underwater or hyperbaric environments: this review summarizes the available literature and was used to test the hypothesis that arterial Po2 under hyperbaric conditions can be predicted from blood gas measurement at 1 atmosphere assuming a constant arterial/alveolar Po2 ratio (a:A). A systematic search was performed on traditional sources including arterial blood gases obtained on humans in hyperbaric or underwater environments. The a:A was calculated at 1 atmosphere absolute (ATA). For each condition, predicted arterial partial pressure of oxygen ([Formula: see text]) at pressure was calculated using the 1 ATA a:A, and the measured [Formula: see text] was plotted against the predicted value with Spearman correlation coefficients. Of 3,640 records reviewed, 30 studies were included: 25 were reports describing values obtained in hyperbaric chambers, and the remaining were collected while underwater. Increased inspired O2 at pressure resulted in increased [Formula: see text], although underlying lung disease in patients treated with hyperbaric oxygen attenuated the rise. [Formula: see text] generally increased only slightly. In breath-hold divers, hyperoxemia generally occurred at maximum depth, with hypoxemia after surfacing. The a:A adequately predicted the [Formula: see text] under various conditions: dry (r = 0.993, P < 0.0001), rest versus exercise (r = 0.999, P < 0.0001), and breathing mixtures (r = 0.995, P < 0.0001). In conclusion, pulmonary oxygenation under hyperbaric conditions can be reliably and accurately predicted from 1 ATA a:A measurements.
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Buceo , Oxigenoterapia Hiperbárica , Análisis de los Gases de la Sangre , Humanos , Oxígeno , Presión Parcial , Intercambio Gaseoso PulmonarRESUMEN
IMPORTANCE: Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. OBJECTIVE: To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389â¯529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40â¯430 patients with established atherosclerosis who were receiving statin treatment. EXPOSURES: ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. MAIN OUTCOME AND MEASURES: The primary study outcome was incident myocardial infarction (MI). RESULTS: Of the 389â¯529 individuals in the primary prevention group, 224â¯097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40â¯430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. CONCLUSIONS AND RELEVANCE: In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.
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Aterosclerosis , Infarto del Miocardio , Apolipoproteínas B , Aterosclerosis/epidemiología , Colesterol , LDL-Colesterol , Estudios de Cohortes , Femenino , Humanos , Lipoproteínas , Masculino , Infarto del Miocardio/epidemiología , Estudios ProspectivosRESUMEN
Mutational activation of KRAS promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of specific activating missense mutations. Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear. Here, we analyze 13,492 samples from these four tumor types to examine allele- and tissue-specific genetic properties associated with oncogenic KRAS mutations. The prevalence of known mutagenic mechanisms partially explains the observed spectrum of KRAS activating mutations. However, there are substantial differences between the observed and predicted frequencies for many alleles, suggesting that biological selection underlies the tissue-specific frequencies of mutant alleles. Consistent with experimental studies that have identified distinct signaling properties associated with each mutant form of KRAS, our genetic analysis reveals that each KRAS allele is associated with a distinct tissue-specific comutation network. Moreover, we identify tissue-specific genetic dependencies associated with specific mutant KRAS alleles. Overall, this analysis demonstrates that the genetic interactions of oncogenic KRAS mutations are allele- and tissue-specific, underscoring the complexity that drives their clinical consequences.