RESUMO
Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.
Assuntos
Doença/genética , Herança Multifatorial/genética , População/genética , RNA Longo não Codificante/genética , Transcriptoma , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Perfilação da Expressão Gênica , Variação Genética , Humanos , Doenças Inflamatórias Intestinais/genética , Especificidade de Órgãos/genética , Locos de Características QuantitativasRESUMO
Polygenic risk scores (PRSs) quantify the contribution of multiple genetic loci to an individual's likelihood of a complex trait or disease. However, existing PRSs estimate this likelihood with common genetic variants, excluding the impact of rare variants. Here, we report on a method to identify rare variants associated with outlier gene expression and integrate their impact into PRS predictions for body mass index (BMI), obesity, and bariatric surgery. Between the top and bottom 10%, we observed a 20.8% increase in risk for obesity (p = 3 × 10-14), 62.3% increase in risk for severe obesity (p = 1 × 10-6), and median 5.29 years earlier onset for bariatric surgery (p = 0.008), as a function of expression outlier-associated rare variant burden when controlling for common variant PRS. We show that these predictions were more significant than integrating the effects of rare protein-truncating variants (PTVs), observing a mean 19% increase in phenotypic variance explained with expression outlier-associated rare variants when compared with PTVs (p = 2 × 10-15). We replicated these findings by using data from the Million Veteran Program and demonstrated that PRSs across multiple traits and diseases can benefit from the inclusion of expression outlier-associated rare variants identified through population-scale transcriptome sequencing.
Assuntos
Herança Multifatorial , Obesidade , Índice de Massa Corporal , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Obesidade/genética , Fenótipo , Fatores de RiscoRESUMO
Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
Assuntos
Aterosclerose/metabolismo , Clonagem Molecular , Ativação do Complemento , Miócitos de Músculo Liso/metabolismo , Fagocitose/fisiologia , Animais , Antígeno CD47/metabolismo , Linhagem da Célula , Proliferação de Células , Complemento C3/genética , Complemento C3/metabolismo , Feminino , Humanos , Inflamação , Macrófagos/metabolismo , Masculino , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/citologia , Placa Aterosclerótica/metabolismo , Análise de Sequência de RNA , Regulação para CimaRESUMO
Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWASs) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMCs) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMCs. We assessed the relevance of HCASMCs to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that may modulate CAD risk through HCASMCs, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMCs, while other annotated genes may have multiple cell and tissue targets. Together, these results provide tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.
Assuntos
Doença da Artéria Coronariana/genética , Vasos Coronários/fisiologia , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Miócitos de Músculo Liso/fisiologia , Locos de Características Quantitativas/genética , Linhagem Celular , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Polimorfismo de Nucleotídeo Único/genética , RiscoRESUMO
AIMS/HYPOTHESIS: Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach. METHODS: Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA1c on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis. RESULTS: Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p = 0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p = 0.49) or HbA1c (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p = 0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA1c, respectively, for associations with atrial fibrillation. CONCLUSIONS/INTERPRETATION: This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA1c and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention. DATA AVAILABILITY: The datasets analysed during the current study are available from the following repository: Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al (2018) GWAS summary statistics for AF (N=60,620 AF cases and 970,216 controls). Center for Statistical Genetics: http://csg.sph.umich.edu/willer/public/afib2018/nielsen-thorolfsdottir-willer-NG2018-AFib-gwas-summary-statistics.tbl.gz.
Assuntos
Fibrilação Atrial/fisiopatologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Fibrilação Atrial/complicações , Fibrilação Atrial/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Genótipo , Hemoglobinas Glicadas/análise , Humanos , Insulina/sangue , Análise da Randomização Mendeliana , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Urine biomarkers reflecting kidney function and handling of dietary sodium and potassium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease, and diabetes mellitus. Knowledge about the genetic determinants of these biomarkers may shed light on pathophysiological mechanisms underlying the development of these diseases. We performed genome-wide association studies of urinary albumin: creatinine ratio (UACR), urinary potassium: creatinine ratio (UK/UCr), urinary sodium: creatinine ratio (UNa/UCr) and urinary sodium: potassium ratio (UNa/UK) in up to 218,450 (discovery) and 109,166 (replication) unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression, and possible genes implicated in the regulation of these biomarkers. After replication, we identified 19 genome-wide significant independent loci associated with UACR, 6 each with UK/UCr and UNa/UCr, and 4 with UNa/UK. In addition to 22 novel associations, we confirmed several established associations, including between the CUBN locus and microalbuminuria. We detected high pairwise genetic correlation across the urinary biomarkers, and between their levels and several physiological measurements. We highlight GIPR, a potential diabetes drug target, as possibly implicated in the genetic control of urinary potassium excretion, and NRBP1, a locus associated with gout, as plausibly involved in sodium and albumin excretion. Overall, we identified 22 novel genome-wide significant associations with urinary biomarkers and confirmed several previously established associations, providing new insights into the genetic basis of these traits and their connection to chronic diseases.
Assuntos
Loci Gênicos , Eliminação Renal/genética , Insuficiência Renal Crônica/genética , Biomarcadores/metabolismo , Biomarcadores/urina , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Potássio/metabolismo , Potássio/urina , Receptores Citoplasmáticos e Nucleares/genética , Receptores dos Hormônios Gastrointestinais/genética , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/urina , Albumina Sérica Humana/metabolismo , Albumina Sérica Humana/urina , Sódio/metabolismo , Sódio/urina , Proteínas de Transporte Vesicular/genéticaRESUMO
PURPOSE OF REVIEW: Large genome-wide association studies (GWAS) have identified variants accounting for a substantial portion of the heritable risk for coronary artery disease (CAD). These studies have catalyzed drug discovery and generated the possibility of improved risk prediction and stratification. Here, we review the current state-of-the art in polygenic risk scores (PRSs) and look to the future, as these scores move towards clinical application. RECENT FINDINGS: Over the last decade, multilocus PRSs for CAD have expanded to include millions of variants and demonstrated strong association with CAD outcomes, even when adjusted for traditional risk factors. Recently, PRSs have shown better prediction of CAD outcomes than any single traditional risk factor alone. Advances in statistical methods used to generate PRSs have improved their predictive ability and transferability between populations with varied ancestries. Initial clinical studies have also demonstrated the potential of genetic information to impact shared decision-making between patients and providers, leading to improved outcomes. SUMMARY: PRSs can improve risk stratification for CAD especially in white/European populations and have the potential to alter routine clinical care. However, unlocking this potential will require additional research in PRSs in nonwhite populations and substantial investment in clinical implementation studies.
Assuntos
Doença da Artéria Coronariana , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
BACKGROUND: The prevalence of obesity and its comorbidities, including type 2 diabetes mellitus (T2DM), is dramatically increasing throughout the world; however, the underlying aetiology is incompletely understood. Genome-wide association studies (GWAS) have identified hundreds of genec susceptibility loci for obesity and T2DM, although the causal genes and mechanisms are largely unknown. SPRY2 is a candidate gene identified in GWAS of body fat percentage and T2DM, and has recently been linked to insulin production in pancreatic ß-cells. In the present study, we aimed to further understand SPRY2 via functional characterisation in HepG2 cells, an in vitro model of human hepatocytes widely used to investigate T2DM and insulin resistance. METHODS: CRISPR-Cas9 genome editing was used to target SPRY2 in HepG2 cells, and the functional consequences of SPRY2 knockout (KO) and overexpression subsequently assessed using glucose uptake and lipid droplet assays, measurement of protein kinase phosphorylation and RNA sequencing. RESULTS: The major functional consequence of SPRY2 KO was a significant increase in glucose uptake, along with elevated lipid droplet accumulation. These changes were attenuated, but not reversed, in cells overexpressing SPRY2. Phosphorylation of protein kinases across key signalling pathways (including Akt and mitogen activated protein kinases) was not altered after SPRY2 KO. Transcriptome profiling in SPRY2 KO and mock (control) cells revealed a number of differentially expressed genes related to cholesterol biosynthesis, cell cycle regulation and cellular signalling pathways. Phospholipase A2 group IIA (PLA2G2A) mRNA level was subsequently validated as significantly upregulated following SPRY2 KO, highlighting this as a potential mediator downstream of SPRY2. CONCLUSION: These findings suggest a role for SPRY2 in glucose and lipid metabolism in hepatocytes and contribute to clarifying the function of this gene in the context of metabolic diseases.
Assuntos
Sistemas CRISPR-Cas , Glucose/metabolismo , Hepatócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Gotículas Lipídicas/metabolismo , Lipogênese , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Perfilação da Expressão Gênica , Células Hep G2 , Hepatócitos/citologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Fosforilação , Transdução de SinaisRESUMO
Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on human and mouse adipogenesis, as well as on cell-to-cell variability in gene expression during this process.
RESUMO
Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on these widely used in vitro models of human and mouse adipogenesis, and on cell-to-cell variability during this process.
Assuntos
Adipogenia , Análise da Expressão Gênica de Célula Única , Transcriptoma , Humanos , Adipócitos/metabolismo , Adipogenia/genética , Tecido Adiposo/metabolismo , Diferenciação Celular , Animais , CamundongosRESUMO
There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. Genome-wide association studies using large population cohorts can be a first step towards identifying patients prone to infectious diseases and targets for new therapies. Genetic variants associated with clinically relevant entities of bacterial and viral infections (e.g., abdominal infections, respiratory infections, and sepsis) in 337,484 participants of the UK Biobank cohort were explored by genome-wide association analyses. Cases (n = 81,179) were identified based on ICD-10 diagnosis codes of hospital inpatient and death registries. Functional annotation was performed using gene expression (eQTL) data. Fifty-seven unique genome-wide significant loci were found, many of which are novel in the context of infectious diseases. Some of the detected genetic variants were previously reported associated with infectious, inflammatory, autoimmune, and malignant diseases or key components of the immune system (e.g., white blood cells, cytokines). Fine mapping of the HLA region revealed significant associations with HLA-DQA1, HLA-DRB1, and HLA-DRB4 locus alleles. PPP1R14A showed strong colocalization with abdominal infections and gene expression in sigmoid and transverse colon, suggesting causality. Shared significant loci across infections and non-infectious phenotypes in the UK Biobank cohort were found, suggesting associations for example between SNPs identified for abdominal infections and CRP, rheumatoid arthritis, and diabetes mellitus. We report multiple loci associated with bacterial and viral infections. A better understanding of the genetic determinants of bacterial and viral infections can be useful to identify patients at risk and in the development of new drugs.
Assuntos
Infecções Bacterianas/epidemiologia , Genes MHC da Classe II , Genes MHC Classe I , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Viroses/epidemiologia , Adulto , Idoso , Bactérias/isolamento & purificação , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Bancos de Espécimes Biológicos/estatística & dados numéricos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Viroses/genética , Viroses/imunologia , Viroses/patologia , Vírus/isolamento & purificaçãoRESUMO
The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2519 out of 5385) of the GWAS loci examined.
Assuntos
Expressão Gênica , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Genes , Humanos , Herança Multifatorial , TranscriptomaRESUMO
Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.
Assuntos
Adipócitos/metabolismo , Distribuição da Gordura Corporal , Proteínas Ativadoras de GTPase/genética , Adipogenia/genética , Animais , Diferenciação Celular/genética , Proteínas Ativadoras de GTPase/metabolismo , Técnicas de Silenciamento de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Resistência à Insulina/genética , Gordura Intra-Abdominal/metabolismo , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Gordura Subcutânea/metabolismoRESUMO
BACKGROUND: Population structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely contains individuals of European ancestry, but the v8 release also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization. RESULTS: Here, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis-eQTL mapping using admixed samples in seven tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe 31 loci (0.02%) where a significant colocalization is called only with one eQTL ancestry adjustment method. Notably, both adjustments produce similar numbers of significant colocalizations within each of two different colocalization methods, COLOC and FINEMAP. Finally, we identify a small subset of eQTL-associated variants highly correlated with local ancestry, providing a resource to enhance functional follow-up. CONCLUSIONS: We provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of the results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach.
Assuntos
Genoma Humano , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Grupos Raciais/genética , Expressão Gênica , Genótipo , HumanosRESUMO
BACKGROUND: PCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. METHODS: We tested the association of the PCSK9 missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of PCSK9 inhibition with higher power at a finer resolution. RESULTS: The T allele of rs11591147 showed a protective effect on hyperlipidemia (odds ratio, 0.63±0.04; P=2.32×10-38), coronary heart disease (odds ratio, 0.73±0.09; P=1.05×10-6), and ischemic stroke (odds ratio, 0.61±0.18; P=2.40×10-3) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24±0.10; P=1.98×10-7). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct PCSK9 inhibition; off-target effects cannot be predicted using this approach. CONCLUSIONS: This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to LDL (low-density lipoprotein) cholesterol, atherosclerosis, and type 2 diabetes mellitus, suggesting that other effects are either small or absent.
Assuntos
Isquemia Encefálica , Mutação de Sentido Incorreto , Pró-Proteína Convertase 9 , Acidente Vascular Cerebral , Idoso , Substituição de Aminoácidos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Estudos de Coortes , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismoRESUMO
OBJECTIVES: The ideal vascular reconstruction strategy for anomalies associated with Tetralogy of Fallot (ToF) is often driven by observations made at the operating table. A method to conduct accurate studies to assess the virtues of a certain surgical technique to guide surgical decisions is found wanting. We hypothesize that patient-specific computed tomography (CT)-based morphometry followed by in silico reconstruction of viable surgical options with haemodynamic function assessment using computational fluid dynamics (CFD) can guide surgical decisions and help forecast functional outcomes without invasive measurements. METHODS: A ToF patient associated with additional left pulmonary artery (LPA) stenosis and a patent ductus arteriosus (PDA) who underwent a successful correction using a single pericardial patch (SPP) was selected as a reference for morphological characterization after 3D anatomical reconstruction from CT images. A second patient with morphological similarities established after scaled, co-registration with the reference patient was selected for virtual correction using the same strategy (i.e. SPP repair). CFD was employed for functional analysis of pulmonary artery (PA) pressure gradients in the baseline preoperative and virtually corrected models, using patient-specific cardiac output and Qp/Qs information. RESULTS: SPP repair was modelled in silico following surgical steps of PDA ligation, creation of an incision along the LPA and main PA (MPA) and finally suturing a rectangular SPP, effectively reducing MPA to LPA angle. Analysis of SPP repair revealed significant reduction in right ventricular outflow tract-LPA pressure gradient with improved left-right PA flow distribution in both patients. CONCLUSIONS: In silico surgery followed by CFD evaluation has the potential in augmenting morphology-guided decisions on surgical strategy and holds promise in preoperatively determining optimal intervention strategy. This is a paradigm-shifting concept to evaluate patient-specific anomalies in a manner more objective than mere visual inspection of anatomical traits from radiology images. Present studies are focused on an analysis with a larger patient cohort to establish a library of ToF patients' successful surgical outcomes to inform morphology-based selection of surgical strategy.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Simulação por Computador , Cirurgia Assistida por Computador/métodos , Tetralogia de Fallot/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/fisiopatologia , Arteriopatias Oclusivas/cirurgia , Criança , Pré-Escolar , Constrição Patológica , Permeabilidade do Canal Arterial/diagnóstico por imagem , Permeabilidade do Canal Arterial/fisiopatologia , Permeabilidade do Canal Arterial/cirurgia , Feminino , Hemodinâmica , Humanos , Imageamento Tridimensional , Valor Preditivo dos Testes , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgia , Interpretação de Imagem Radiográfica Assistida por Computador , Tetralogia de Fallot/fisiopatologia , Tetralogia de Fallot/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Military personnel and civilians living in areas of armed conflict have increased risk of exposure to blast overpressures that can cause significant hearing loss and/or brain injury. The equipment used to simulate comparable blast overpressures in animal models within laboratory settings is typically very large and prohibitively expensive. NEW METHOD: To overcome the fiscal and space limitations introduced by previously reported blast wave generators, we developed a compact, low-cost blast wave generator to investigate the effects of blast exposures on the auditory system and brain. RESULTS: The blast wave generator was constructed largely from off the shelf components, and reliably produced blasts with peak sound pressures of up to 198dB SPL (159.3kPa) that were qualitatively similar to those produced from muzzle blasts or explosions. Exposure of adult rats to 3 blasts of 188dB peak SPL (50.4kPa) resulted in significant loss of cochlear hair cells, reduced outer hair cell function and a decrease in neurogenesis in the hippocampus. COMPARISON TO EXISTING METHODS: Existing blast wave generators are typically large, expensive, and are not commercially available. The blast wave generator reported here provides a low-cost method of generating blast waves in a typical laboratory setting. CONCLUSIONS: This compact blast wave generator provides scientists with a low cost device for investigating the biological mechanisms involved in blast wave injury to the rodent cochlea and brain that may model many of the damaging effects sustained by military personnel and civilians exposed to intense blasts.