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Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
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Resolving the molecular processes that mediate genetic risk remains a challenge because most disease-associated variants are non-coding and functional characterization of these signals requires knowledge of the specific tissues and cell-types in which they operate. To address this challenge, we developed a framework for integrating tissue-specific gene expression and epigenomic maps to obtain "tissue-of-action" (TOA) scores for each association signal by systematically partitioning posterior probabilities from Bayesian fine-mapping. We applied this scheme to credible set variants for 380 association signals from a recent GWAS meta-analysis of type 2 diabetes (T2D) in Europeans. The resulting tissue profiles underscored a predominant role for pancreatic islets and, to a lesser extent, adipose and liver, particularly among signals with greater fine-mapping resolution. We incorporated resulting TOA scores into a rule-based classifier and validated the tissue assignments through comparison with data from cis-eQTL enrichment, functional fine-mapping, RNA co-expression, and patterns of physiological association. In addition to implicating signals with a single TOA, we found evidence for signals with shared effects in multiple tissues as well as distinct tissue profiles between independent signals within heterogeneous loci. Lastly, we demonstrated that TOA scores can be directly coupled with eQTL colocalization to further resolve effector transcripts at T2D signals. This framework guides mechanistic inference by directing functional validation studies to the most relevant tissues and can gain power as fine-mapping resolution and cell-specific annotations become richer. This method is generalizable to all complex traits with relevant annotation data and is made available as an R package.
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Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Tecido Adiposo/metabolismo , Mapeamento Cromossômico , Análise por Conglomerados , Biologia Computacional , Elementos Facilitadores Genéticos , Epigenômica , Genoma Humano , Humanos , Ilhotas Pancreáticas/metabolismo , Desequilíbrio de Ligação , Fígado/metabolismo , Modelos Estatísticos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , ProbabilidadeRESUMO
OBJECTIVES: To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. METHODS: Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing. RESULTS: mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes. CONCLUSIONS: The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended.
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DNA Mitocondrial , Osteoartrite do Joelho , Humanos , DNA Mitocondrial/genética , Osteoartrite do Joelho/genética , Espécies Reativas de Oxigênio , Estudos Prospectivos , Mitocôndrias/genética , Inflamação/metabolismoRESUMO
AIMS/HYPOTHESIS: Sleep, diet and exercise are fundamental to metabolic homeostasis. In this secondary analysis of a repeated measures, nutritional intervention study, we tested whether an individual's sleep quality, duration and timing impact glycaemic response to a breakfast meal the following morning. METHODS: Healthy adults' data (N = 953 [41% twins]) were analysed from the PREDICT dietary intervention trial. Participants consumed isoenergetic standardised meals over 2 weeks in the clinic and at home. Actigraphy was used to assess sleep variables (duration, efficiency, timing) and continuous glucose monitors were used to measure glycaemic variation (>8000 meals). RESULTS: Sleep variables were significantly associated with postprandial glycaemic control (2 h incremental AUC), at both between- and within-person levels. Sleep period time interacted with meal type, with a smaller effect of poor sleep on postprandial blood glucose levels when high-carbohydrate (low fat/protein) (pinteraction = 0.02) and high-fat (pinteraction = 0.03) breakfasts were consumed compared with a reference 75 g OGTT. Within-person sleep period time had a similar interaction (high carbohydrate: pinteraction = 0.001, high fat: pinteraction = 0.02). Within- and between-person sleep efficiency were significantly associated with lower postprandial blood glucose levels irrespective of meal type (both p < 0.03). Later sleep midpoint (time deviation from midnight) was found to be significantly associated with higher postprandial glucose, in both between-person and within-person comparisons (p = 0.035 and p = 0.051, respectively). CONCLUSIONS/INTERPRETATION: Poor sleep efficiency and later bedtime routines are associated with more pronounced postprandial glycaemic responses to breakfast the following morning. A person's deviation from their usual sleep pattern was also associated with poorer postprandial glycaemic control. These findings underscore sleep as a modifiable, non-pharmacological therapeutic target for the optimal regulation of human metabolic health. Trial registration ClinicalTrials.gov NCT03479866.
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Glicemia/metabolismo , Desjejum , Dieta , Privação do Sono/sangue , Adolescente , Adulto , Idoso , Feminino , Controle Glicêmico , Índice Glicêmico , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial/fisiologia , Adulto JovemRESUMO
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
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Envelhecimento/genética , Peso ao Nascer/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feto/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Antropometria , Pressão Sanguínea/genética , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Loci Gênicos/genética , Variação Genética/genética , Impressão Genômica/genética , Genótipo , Glucose/metabolismo , Glicogênio/biossíntese , Humanos , Insulina/metabolismo , Masculino , Fenótipo , Transdução de SinaisRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1007813.].
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Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.
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Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/genética , Povo Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , População Branca/genéticaRESUMO
Osteoarthritis (OA) is the most common rheumatic pathology and is characterized primarily by articular cartilage degradation. Despite its high prevalence, there is no effective therapy to slow disease progression or regenerate the damaged tissue. Therefore, new diagnostic and monitoring tests for OA are urgently needed, which would also promote the development of alternative therapeutic strategies. In the present study, we have performed an iTRAQ-based quantitative proteomic analysis of secretomes from healthy human articular cartilage explants, comparing their protein profile to those from unwounded (early disease) and wounded (advanced disease) zones of osteoarthritic tissue. This strategy allowed us to identify a panel of 76 proteins that are distinctively released by the diseased tissue. Clustering analysis allowed the classification of proteins according to their different profile of release from cartilage. Among these proteins, the altered release of osteoprotegerin (decreased in OA) and periostin (increased in OA), both involved in bone remodelling processes, was verified in further analyses. Moreover, periostin was also increased in the synovial fluid of OA patients. Altogether, the present work provides a novel insight into the mechanisms of human cartilage degradation and a number of new cartilage-characteristic proteins with possible biomarker value for early diagnosis and prognosis of OA.
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Cartilagem Articular/metabolismo , Osteoartrite/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Western Blotting , Cartilagem Articular/patologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Osteoartrite/diagnóstico , Osteoartrite/genética , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Proteoma/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Líquido Sinovial/metabolismo , Espectrometria de Massas em Tandem , Técnicas de Cultura de TecidosRESUMO
Osteoarthritis (OA) is the most common rheumatic disease and one of the most disabling pathologies worldwide. To date, the diagnostic methods of OA are very limited, and there are no available medications capable of halting its characteristic cartilage degeneration. Therefore, there is a significant interest in new biomarkers useful for the early diagnosis, prognosis, and therapeutic monitoring. In the recent years, protein microarrays have emerged as a powerful proteomic tool to search for new biomarkers. In this study, we have used two concepts for generating protein arrays, antigen microarrays, and NAPPA (nucleic acid programmable protein arrays), to characterize differential autoantibody profiles in a set of 62 samples from OA, rheumatoid arthritis (RA), and healthy controls. An untargeted screen was performed on 3840 protein fragments spotted on planar antigen arrays, and 373 antigens were selected for validation on bead-based arrays. In the NAPPA approach, a targeted screening was performed on 80 preselected proteins. The autoantibody targeting CHST14 was validated by ELISA in the same set of patients. Altogether, nine and seven disease related autoantibody target candidates were identified, and this work demonstrates a combination of these two array concepts for biomarker discovery and their usefulness for characterizing disease-specific autoantibody profiles.
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Autoanticorpos/sangue , Osteoartrite/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise Serial de Proteínas/métodos , Reprodutibilidade dos Testes , Sulfotransferases/imunologiaRESUMO
OBJECTIVE: Alterations in DNA methylation patterns have been found to correlate with several diseases including osteoarthritis (OA). The aim of this study was to identify, for the first time, the genome-wide DNA methylation profiles of human articular chondrocytes from OA cartilage and healthy control cartilage samples. METHODS: DNA methylation profiling was performed using Illumina Infinium HumanMethylation27 in 25 patients with OA and 20 healthy controls. Subsequent validation was performed by genome-wide expression analysis using the Affymetrix Human Gene 1.1 ST array in an independent cohort of 24 patients with OA. Finally, the most consistent genes in both assays were amplified by quantitative reverse transcriptase PCR in a validation cohort of 48 patients using microfluidic real-time quantitative PCR. Appropriate bioinformatics analyses were carried out using R bioconductor software packages and qBase plus software from Biogazelle. RESULTS: We found 91 differentially methylated (DM) probes, which permitted us to separate patients with OA from healthy controls. Among the patients with OA, we detected 1357 DM probes that identified a tight cluster of seven patients who were different from the rest. This cluster was also identified by genome-wide expression in which 450 genes were differentially expressed. Further validation of the most consistent genes in an independent cohort of patients with OA permitted us to identify this cluster, which was characterised by increased inflammatory processes. CONCLUSIONS: We were able to identify a tight subgroup of patients with OA, characterised by an increased inflammatory response that could be regulated by epigenetics. The identification and isolation of this subgroup may be critical for the development of effective treatment and disease prevention.
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Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Metilação de DNA , Osteoartrite do Joelho/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
Circulating microRNAs (miRNAs) are linked to the onset and progression of type 1 diabetes mellitus (T1DM), thus representing potential disease biomarkers. In this study, we employed a multiplatform sequencing approach to analyze circulating miRNAs in an extended cohort of prospectively evaluated recent-onset T1DM individuals from the INNODIA consortium. Our findings reveal that a set of miRNAs located within T1DM susceptibility chromosomal locus 14q32 distinguishes two subgroups of individuals. To validate our results, we conducted additional analyses on a second cohort of T1DM individuals, confirming the identification of these subgroups, which we have named cluster A and cluster B. Remarkably, cluster B T1DM individuals, who exhibit increased expression of a set of 14q32 miRNAs, show better glycemic control and display a different blood immunomics profile. Our findings suggest that this set of circulating miRNAs can identify two different T1DM subgroups with distinct blood immunomics at baseline and clinical outcomes during follow-up.
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Cromossomos Humanos Par 14 , MicroRNA Circulante , Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/sangue , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Masculino , Feminino , Cromossomos Humanos Par 14/genética , Adulto , Adolescente , Loci Gênicos , Adulto Jovem , MicroRNAs/genética , MicroRNAs/sangue , Biomarcadores/sangue , Criança , Predisposição Genética para DoençaRESUMO
Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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Povo Asiático , Neoplasias Colorretais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , População Branca , Humanos , Neoplasias Colorretais/genética , Povo Asiático/genética , População Branca/genética , Sequenciamento do Exoma , Estudos de Casos e Controles , Transcriptoma , Mapeamento Cromossômico , Masculino , Feminino , População do Leste AsiáticoRESUMO
CONTEXT: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood. OBJECTIVE: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. METHODS: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D. RESULTS: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. CONCLUSION: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.
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Diabetes Mellitus Tipo 2 , Dieta , Peptídeo 1 Semelhante ao Glucagon , Estilo de Vida , Estado Pré-Diabético , Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Estudos Transversais , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Estado Pré-Diabético/metabolismo , Idoso , Adulto , Resistência à Insulina , Jejum/sangue , Obesidade/sangue , Obesidade/metabolismo , Estudos de Coortes , Glicemia/metabolismo , Glicemia/análise , Adiposidade/fisiologiaRESUMO
Okadaic acid (OA), produced by dinoflagellates during harmful algal blooms (HAB), belongs to the Diarrheic Shellfish Poisoning toxins that cause gastrointestinal symptoms in humans after consumption. In the present work, Ruditapes decussatus haemocytes were selected to evaluate the effect of OA on cell viability, enzymatic status and immune capacity through the measure by flow cytometry of apoptosis-cell death, non-specific esterase activity and phagocytosis. In order to compare different exposure conditions, two experiments were developed: in vitro exposure to OA and HAB simulation by feeding clams with the OA producer, Prorocentrum lima. Apoptosis was not OA dose-dependent and cell death increased in both assays. Phagocytosis of latex beads and esterase activity decreased in haemocytes incubated with OA. In contrast, esterases increased during the feeding with P. lima. Our results showed that OA and the simulated HAB caused damages on haemocyte functions and viability.
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Bivalves/efeitos dos fármacos , Dinoflagellida/metabolismo , Proliferação Nociva de Algas/fisiologia , Hemócitos/efeitos dos fármacos , Ácido Okadáico/toxicidade , Animais , Apoptose/efeitos dos fármacos , Bioensaio , Bivalves/citologia , Bivalves/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Esterases/antagonistas & inibidores , Esterases/metabolismo , Hemócitos/citologia , Humanos , Microesferas , Ácido Okadáico/metabolismo , Fagocitose/efeitos dos fármacosRESUMO
The extraordinary progress experienced by sequencing technologies and bioinformatics has made the development of omic studies virtually ubiquitous in all fields of life sciences nowadays. However, scientific attention has been quite unevenly distributed throughout the different branches of the tree of life, leaving molluscs, one of the most diverse animal groups, relatively unexplored and without representation within the narrow collection of well established model organisms. Within this Phylum, bivalve molluscs play a fundamental role in the functioning of the marine ecosystem, constitute very valuable commercial resources in aquaculture, and have been widely used as sentinel organisms in the biomonitoring of marine pollution. Yet, it has only been very recently that this complex group of organisms became a preferential subject for omic studies, posing new challenges for their integrative characterization. The present contribution aims to give a detailed insight into the state of the art of the omic studies and functional information analysis of bivalve molluscs, providing a timely perspective on the available data resources and on the current and prospective applications for the biomonitoring of harmful marine compounds.
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Bivalves/genética , Bivalves/metabolismo , Monitoramento Ambiental , Animais , Ecossistema , HumanosRESUMO
Okadaic Acid (OA) constitutes the main active principle in Diarrhetic Shellfish Poisoning (DSP) toxins produced during Harmful Algal Blooms (HABs), representing a serious threat for human consumers of edible shellfish. Furthermore, OA conveys critical deleterious effects for marine organisms due to its genotoxic potential. Many efforts have been dedicated to OA biomonitoring during the last three decades. However, it is only now with the current availability of detailed molecular information on DNA organization and the mechanisms involved in the maintenance of genome integrity, that a new arena starts opening up for the study of OA contamination. In the present work we address the links between OA genotoxicity and chromatin by combining Next Generation Sequencing (NGS) technologies and bioinformatics. To this end, we introduce CHROMEVALOAdb, a public database containing the chromatin-associated transcriptome of the mussel Mytilus galloprovincialis (a sentinel model organism) in response to OA exposure. This resource constitutes a leap forward for the development of chromatin-based biomarkers, paving the road towards the generation of powerful and sensitive tests for the detection and evaluation of the genotoxic effects of OA in coastal areas.
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Bases de Dados Factuais , Mutagênicos/análise , Mytilus/genética , Ácido Okadáico/análise , Animais , Carcinógenos/análise , Carcinógenos/isolamento & purificação , Carcinógenos/toxicidade , Cromatina/metabolismo , Monitoramento Ambiental/métodos , Humanos , Testes de Mutagenicidade/métodos , Mutagênicos/isolamento & purificação , Mutagênicos/toxicidade , Ácido Okadáico/toxicidade , Análise de Sequência de DNA , TranscriptomaRESUMO
Okadaic acid (OA) is one of the most common and highly distributed marine toxins. It can be accumulated in several molluscs and other marine organisms and cause acute gastrointestinal symptoms after oral consumption by humans, called diarrheic shellfish poisoning. However other toxic effects beyond these gastrointestinal symptoms were also reported. Thus, OA was found to induce important chromosomal abnormalities and other genetic injuries that can lead to severe pathologies, including cancer. Furthermore, the relationship between OA and carcinogenic processes has been previously demonstrated in in vivo studies with rodents, and also suggested in human epidemiological studies. In this context, further research is required to better understand the underlying mechanisms of OA-related tumourigenesis. In a previous study, we identified 247 genes differentially expressed in SHSY5Y neuroblastoma cells exposed to 100nM OA at different times (3, 24 and 48h) by means of suppression subtractive hybridization. These genes were involved in relevant cell functions such as signal transduction, cell cycle, metabolism, and transcription and translation processes. However, due to the high potential percentage of false positives that may be obtained by this approach, results from SSH are recommended to be analyzed by an independent method. In the present study, we selected ten genes related to cancer initiation or progression, directly or indirectly, for further quantitative PCR analysis (ANAPC13, PTTG1, CALM2, CLU, HN1, MALAT1, MAPRE2, MLLT11, SGA-81M and TAX1BP1). Results obtained showed important alterations in the expression patterns of all the genes evaluated at one or more treatment times, providing, for the first time, a possible explanation at the molecular level of the potential relationship between the consumption of OA-contaminated shellfish and the incidence of different cancers in humans. Nevertheless, given the complexity of this process, more exhaustive studies are required before drawing any final conclusion.
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Aberrações Cromossômicas/induzido quimicamente , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Toxinas Marinhas/toxicidade , Neurônios/efeitos dos fármacos , Ácido Okadáico/toxicidade , Carcinógenos/toxicidade , Ciclo Celular , Linhagem Celular , Transformação Celular Neoplásica/induzido quimicamente , Humanos , Neurônios/fisiologia , Hibridização de Ácido Nucleico , Intoxicação por Frutos do MarRESUMO
Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Obesidade/metabolismo , Fenótipo , ColesterolRESUMO
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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Neoplasias Colorretais , População do Leste Asiático , População Europeia , Humanos , Neoplasias Colorretais/genética , População do Leste Asiático/genética , População Europeia/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Multiômica , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.