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PLoS PathogensVolume 13, Issue 2, February 2017, Article number e1006220

OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed CUBANS(Article)(Open Access)

  • Sierra, B.,
  • Triska, P.,
  • Soares, P.,
  • Garcia, G.,
  • Perez, A.B.,
  • Aguirre, E.,
  • Oliveira, M.,
  • Cavadas, B.,
  • Regnault, B.,
  • Alvarez, M.,
  • Ruiz, D.,
  • Samuels, D.C.,
  • Sakuntabhai, A.,
  • Pereira, L.,
  • Guzman, M.G.
  • View Correspondence (jump link)
  • aVirology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK), Havana, Cuba
  • bi3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  • cInstituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal
  • dInstituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
  • eEukaryote Genotyping Platform, Genopole Pasteur Institute, Paris, France
  • fVanderbilt Genetics Institute, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
  • gFunctional Genetics of Infectious Diseases Unit, Pasteur Institute, Paris, France
  • hFaculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal

Abstract

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. © 2017 Sierra et al.

Indexed keywords

EMTREE drug terms:cell nucleus receptorcollagen type 5ficolinmessenger RNAoxysterol binding brotein Like 10proteinretinoid X receptor alphashort hairpin RNAtranscriptomeunclassified drugoxysterol binding proteinretinoid X receptor alphasteroid receptor
EMTREE medical terms:ArticleBlack personcohort analysiscontrolled studyCubaCubancytokine productiondengueDengue virusDengue virus 2disease coursedisease severityethnic differencegenegene expressiongene frequencygenetic susceptibilitygenome-wide association studygenotypehaplotypehumanhuman celllipid metabolismmajor clinical studymulticenter studynonhumanoxysterol binding protein like 10 genepopulation structurereal time polymerase chain reactionretinoid X receptor alpha genereverse transcription polymerase chain reactionsingle nucleotide polymorphismvirus cell interactionvirus entryvirus loadDNA microarrayethnologygenetic predispositiongeneticslipid metabolismpolymerase chain reactionsevere dengue
MeSH:African Continental Ancestry GroupCubaGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansLipid MetabolismOligonucleotide Array Sequence AnalysisPolymerase Chain ReactionPolymorphism, Single NucleotideReceptors, SteroidRetinoid X Receptor alphaSevere Dengue

Chemicals and CAS Registry Numbers:

protein, 67254-75-5; retinoid X receptor alpha, 465567-51-5;

oxysterol binding protein; Receptors, Steroid; Retinoid X Receptor alpha

Funding details

Funding sponsor Funding number Acronym
Seventh Framework Programmehttps://ec.europa.eu/research/fp7/index_en.cfm],282378
Quad Cities Community Foundation
SFRH/BD/95626/2013
Research Executive Agency290344REA
Fuel Cell Technologies ProgramFCT
Seventh Framework Programme
POCI-01-0145-FEDER-007274
COMPETE

  • 1

    The research leading to these results has received funding from the European Commission Seventh Framework Programme [https://ec.europa.eu/research/fp7/index_en.cfm] for the DENFREE project under Grant Agreement no. 282378. PT had a PhD grant from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (http://ec.europa.eu/research/mariecurieactions/) under REA grant agreement no. 290344 (EUROTAST) and MO a PhD grant from FCT, The Portuguese Foundation for Science and Technology (https://www.fct.pt/fct.phtml.en) with reference SFRH/BD/95626/2013. I3S is financed by FEDER funds through COMPETE 2020, Portugal 2020, and by Portuguese funds through FCT/Minist?rio da Ci?ncia, Tecnologia e Inova??o (POCI-01-0145-FEDER-007274). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We dedicate this paper to the memory of Professor Gustavo Kour?. We thank all the Cuban individuals from Havana and Guantanamo cities who agreed to participate in this study. The authors express thanks to Dr Torreblanca from the Centre of Hygiene and Epidemiology of Guantanamo City, to Dr. Raiza Martinez from the Salvador Allende Hospital, and to Dr. Rosa Martinez and technicians Barbara Marrero and Jose Rodriguez from the Pedro Kour? Tropical Medicine Institute, for their support in the samples collection. The authors also thank the technician Laure Lem?e, from the Eukaryote Genotyping Platform Institut Pasteur, for her helpful support with the genotyping. Thanks also to Dr. Daniel Limonta for his helpful reviewing of this paper.

  • ISSN: 15537366
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1371/journal.ppat.1006220
  • PubMed ID: 28241052
  • Document Type: Article
  • Publisher: Public Library of Science

  Sierra, B.; Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK), Havana, Cuba;
© Copyright 2017 Elsevier B.V., All rights reserved.

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