RESUMO
Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.
Assuntos
Metabolismo dos Lipídeos/genética , Receptores de Esteroides/genética , Receptor X Retinoide alfa/genética , Dengue Grave/genética , População Negra/genética , Cuba/etnologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Dengue Grave/etnologiaRESUMO
This article examines the successes and limits of the macroeconomic and fiscal reforms under the Fernando Henrique Cardoso Administration in Brazil. The author begins by studying factors that contributed to macroeconomic difficulties prior to 1995, then proceeds to examine how the Real Plan enabled the Cardoso Administration to control interference by State Governors in the national economy. The article then describes how former President Cardoso's policies generated the current ''fiscal straitjacket'' in Brazil, and concludes by discussing how the Cardoso government's legacy may continue to constrain action by future Brazilian Administrations.
Dans cet article, on examine les succès et les limites des réformes macroéconomiques et fiscales du gouvernement sous la présidence de Fernando Henrique Cardoso. On analyse d'abord les facteurs responsables des difficultés macroéconomiques avant 1995, ainsi que la façon dont le Plan Real a permis au gouvernement FHC de contrôler l'ingérence des exécutifs régionaux dans l'économie nationale. Ensuite on voit comment les politiques de président ont créé le ''carcan fiscal'' où se trouve actuellement le Brésil et montre que la gestion écoulée pourra restreindre l'action des gouvernements brésiliens à venir.