OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans
| Autor: | Mayling Alvarez, María G. Guzmán, Ana B. Pérez, David C. Samuels, Béatrice Regnault, Gissel García, Didye Ruiz, Marisa Oliveira, Beatriz Sierra, Luísa Pereira, Eglys Aguirre, Petr Triska, Anavaj Sakuntabhai, Pedro Soares, Bruno Cavadas |
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| Přispěvatelé: | Pedro Kouri Institute of Tropical Medicine, Universidade do Porto = University of Porto, Instituto de Investigação e Inovação em Saúde (I3S), Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vanderbilt University [Nashville], Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Candidate gene Receptors Steroid Viral Diseases Heredity Thai People Gene Expression Genome-wide association study Dengue virus medicine.disease_cause MESH: Retinoid X Receptor alpha Polymerase Chain Reaction Biochemistry Dengue fever Dengue Fever MESH: Cuba MESH: Genotype Medicine and Health Sciences Ethnicities Binding proteins lcsh:QH301-705.5 Determinants Oligonucleotide Array Sequence Analysis MESH: Lipid Metabolism Genetics Genome-wide association MESH: Polymorphism Single Nucleotide MESH: Genetic Predisposition to Disease Cuba Genomics Lipids [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] 3. Good health SNP genotyping Virus Genetic Mapping Infectious Diseases [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology Infection Transcriptome Analysis Research Article Neglected Tropical Diseases lcsh:Immunologic diseases. Allergy Genotype Liver-x-receptors 030106 microbiology Immunology Genetic admixture Black People Replication Single-nucleotide polymorphism MESH: Severe Dengue Admixture Biology Microbiology Polymorphism Single Nucleotide 03 medical and health sciences Virology Genetic predisposition medicine Genome-Wide Association Studies Humans Genetic Predisposition to Disease [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology Severe Dengue Molecular Biology Retinoid X Receptor alpha MESH: Humans [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE] Biology and Life Sciences Computational Biology Human Genetics MESH: Polymerase Chain Reaction medicine.disease Lipid Metabolism Tropical Diseases Genome Analysis 030104 developmental biology Metabolism lcsh:Biology (General) Haplotypes Genes [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Susceptibility People and Places MESH: Genome-Wide Association Study MESH: Oligonucleotide Array Sequence Analysis Parasitology Population Groupings [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie MESH: African Continental Ancestry Group [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] lcsh:RC581-607 Genome-Wide Association Study Africans MESH: Receptors Steroid |
| Zdroj: | PLoS Pathogens PLoS Pathogens, 2017, 13 (2), pp.e1006220. ⟨10.1371/journal.ppat.1006220⟩ Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP PLoS Pathogens, Public Library of Science, 2017, 13 (2), pp.e1006220. ⟨10.1371/journal.ppat.1006220⟩ PLoS Pathogens, Vol 13, Iss 2, p e1006220 (2017) |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1006220⟩ |
| Popis: | 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. Author summary Dengue is a concern of worldwide health authorities given the increase on virus and vector dispersions. So far only one traditional GWAS survey has been performed in Vietnamese children. This disease is also epidemic in tropical and subtropical regions of the Americas, where most populations descend from a dynamic admixture between African, European and Native American backgrounds. Empirical evidence claimed that African descent was protective against dengue haemorrhagic phenotype in the Cuban population, and this study is the first to apply admixture mapping to identify candidate genes that confer African protection. We also present evidence that two candidate genes, OSBPL10 and RXRA, are differentially expressed along dengue disease progression in Cuban patients and in a Thai dengue transcriptome dataset, and directly show that knockdown of OSBPL10 gene expression leads to a significant reduction in DENV2 replication. A very important overall result of our work is that it provides a unifying framework for many genes that have been said to be protective in dengue. Our evidence places the LXR/RXR activation pathway at the center of natural dengue protection, and supports pursuing therapeutic techniques involving synthetic ligands of nuclear receptor genes or kinases inhibitors that interact with proteins involved in lipid metabolism. |
| Databáze: | OpenAIRE |
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