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1.
Genome Res ; 28(12): 1812-1825, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30446528

RESUMEN

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus.


Asunto(s)
Empalme Alternativo , Aminopeptidasas/genética , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno/genética , Virus de la Influenza A , Gripe Humana/genética , Gripe Humana/virología , Adolescente , Adulto , Mapeo Cromosómico , Biología Computacional/métodos , Células Dendríticas/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Pruebas Genéticas , Variación Genética , Humanos , Interferón Tipo I/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , Anotación de Secuencia Molecular , Monocitos/metabolismo , Sitios de Carácter Cuantitativo , Transcriptoma , Adulto Joven
2.
Hum Mol Genet ; 23(4): 870-7, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24067533

RESUMEN

Using a Drosophila model of Alzheimer's disease (AD), we systematically evaluated 67 candidate genes based on AD-associated genomic loci (P < 10(-4)) from published human genome-wide association studies (GWAS). Genetic manipulation of 87 homologous fly genes was tested for modulation of neurotoxicity caused by human Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 genes enhanced Tau neurotoxicity, and in most cases reciprocal activation of gene expression suppressed Tau toxicity. Our screen implicates cindr, the fly ortholog of the human CD2AP AD susceptibility gene, as a modulator of Tau-mediated disease mechanisms. Importantly, we also identify the fly orthologs of FERMT2 and CELF1 as Tau modifiers, and these loci have been independently validated as AD susceptibility loci in the latest GWAS meta-analysis. Both CD2AP and FERMT2 have been previously implicated with roles in cell adhesion, and our screen additionally identifies a fly homolog of the human integrin adhesion receptors, ITGAM and ITGA9, as a modifier of Tau neurotoxicity. Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas tau/genética , Animales , Animales Modificados Genéticamente , Antígeno CD11b/genética , Modelos Animales de Enfermedad , Proteínas de Drosophila/metabolismo , Técnicas de Silenciamiento del Gen , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Integrinas/genética , Interferencia de ARN
3.
Am J Hum Genet ; 88(2): 232-8, 2011 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-21295279

RESUMEN

We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Drosophila/genética , Genoma , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/patología , Polimorfismo de Nucleótido Simple/genética , Animales , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Transportador de Glucosa de Tipo 1/genética , Humanos , Fenotipo , Sitios de Carácter Cuantitativo , Transducción de Señal , Proteínas tau/genética
4.
BMJ Glob Health ; 6(12)2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34969680

RESUMEN

INTRODUCTION: The high burden of emergency medical conditions has not been met with adequate financial and political prioritisation especially in low and middle-income countries. We examined the factors that have shaped the priority of global emergency care and highlight potential responses by emergency care advocates. METHODS: We conducted semistructured interviews with key experts in global emergency care practice, public health, health policy and advocacy. We then applied a policy framework based on political ethnography and content analysis to code for underlying themes. RESULTS: We identified problem definition, coalition building, paucity of data and positioning, as the main challenges faced by emergency care advocates. Problem definition remains the key issue, with divergent ideas on what emergency care is, should be and what solutions are to be prioritised. Proponents have struggled to portray the urgency of the issue in a way that commands action from decision-makers. The lack of data further limits their effectiveness. However, there is much reason for optimism given the network's commitment to the issue, the emerging leadership and the existence of policy windows. CONCLUSION: To improve global priority for emergency care, proponents should take advantage of the emerging governance structure and build consensus on definitions, generate data-driven solutions, find strategic framings and engage with non-traditional allies.


Asunto(s)
Servicios Médicos de Urgencia , Formulación de Políticas , Política de Salud , Humanos , Liderazgo , Salud Pública
5.
Science ; 343(6175): 1246980, 2014 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-24604203

RESUMEN

Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-ß (IFN-ß). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.


Asunto(s)
Células Dendríticas/inmunología , Interacción Gen-Ambiente , Interacciones Huésped-Patógeno/genética , Factor 7 Regulador del Interferón/genética , Factores de Transcripción STAT/genética , Adulto , Enfermedades Autoinmunes/genética , Enfermedades Transmisibles/genética , Células Dendríticas/efectos de los fármacos , Escherichia coli , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Células HEK293 , Humanos , Virus de la Influenza A , Interferón beta/farmacología , Lipopolisacáridos/inmunología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Transcriptoma , Adulto Joven
6.
Lancet Diabetes Endocrinol ; 5(8): 622-667, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28688818
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