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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.
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
3.
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
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