title: OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans.
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.
authors.affiliation: Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sierra
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Petr
authors.initials: P
authors.lastname: Triska
authors.affiliation: Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Soares
authors.affiliation: Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
authors.forename: Gissel
authors.initials: G
authors.lastname: Garcia
authors.affiliation: Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Perez
authors.affiliation: Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
authors.forename: Eglys
authors.initials: E
authors.lastname: Aguirre
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Eukaryote Genotyping Platform, Genopole Pasteur Institute, Paris, France.|Functional Genetics of Infectious Diseases Unit, Pasteur Institute, Paris, France.
authors.forename: Marisa
authors.identifier: 0000-0002-3214-0759
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Cavadas
authors.affiliation: Eukaryote Genotyping Platform, Genopole Pasteur Institute, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Regnault
authors.affiliation: Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
authors.forename: Mayling
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
authors.forename: Didye
authors.initials: D
authors.lastname: Ruiz
authors.affiliation: Vanderbilt Genetics Institute, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: David C
authors.identifier: 0000-0003-3529-7791
authors.initials: DC
authors.lastname: Samuels
authors.affiliation: Functional Genetics of Infectious Diseases Unit, Pasteur Institute, Paris, France.
authors.forename: Anavaj
authors.identifier: 0000-0001-9099-6937
authors.initials: A
authors.lastname: Sakuntabhai
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.|Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal.
authors.forename: Luisa
authors.identifier: 0000-0002-4271-1527
authors.initials: L
authors.lastname: Pereira
authors.affiliation: Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Guzman
mesh_terms: D044383:Black People / Q000235:genetics; D003462:Cuba / Q000208:ethnology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011987:Receptors, Steroid / Q000235:genetics*; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D019595:Severe Dengue / Q000208:ethnology / Q000235:genetics*; D000098825:Oxysterol Binding Proteins
chemical_list: D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D000098825:Oxysterol Binding Proteins