Genome-Wide Association Study Identifies Single Nucleotide Polymorphism in DYRK1A Associated with Replication of HIV-1 in Monocyte-Derived Macrophages
| Autor: | Perry D. Moerland, Jean-François Zagury, Cédric Coulonges, Margit Sieberer, Daniëlle van Manen, Jeremy J. Martinson, Sophie Limou, Jacques Fellay, Ruben van 't Slot, Hanneke Schuitemaker, Joshua T. Herbeck, Jantine G. Sietzema, Yvonne van Remmerden, Sebastiaan Bol, Angélique B. van 't Wout |
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| Přispěvatelé: | Faculteit der Geneeskunde, Landsteiner Laboratory, Sanquin Research, Department of Experimental Immunology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Center for Infection and Immunity Amsterdam (CINIMA), Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Netherlands Bioinformatics Center (NBIC), Netherlands Bioinformatics Center, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Microbiology, University of Washington School of Medicine, Center for Human Genome Variation, Duke University [Durham], Complex Genetics Section, Department of Biomedical Genetics, University Medical Center [Utrecht], Department of Human Genetics, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The authors acknowledge funding from the Landsteiner Foundation Blood Research (registration number 0526) and the European Union (Marie Curie International Reintegration Grant 029167). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute. UO1-AI-35042, UL1-RR025005 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041., Guellaen, Georges, University of Amsterdam [Amsterdam] (UvA)-Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-Center for Infection and Immunity Amsterdam (CINIMA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Amsterdam institute for Infection and Immunity, Amsterdam Public Health, Epidemiology and Data Science, Other departments, Experimental Immunology |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
lcsh:Medicine HIV Infections Genome-wide association study Virus Replication Linkage Disequilibrium Monocytes 0302 clinical medicine MESH: Animals lcsh:Science Cells Cultured 0303 health sciences Multidisciplinary MESH: Enzyme-Linked Immunosorbent Assay MESH: Feces Genomics Middle Aged Protein-Tyrosine Kinases 3. Good health SNP genotyping Host-Pathogen Interaction MESH: Entamoebiasis Medicine Infectious diseases Female Research Article Adult medicine.medical_specialty Immune Cells Immunology Retrovirology and HIV immunopathogenesis Single-nucleotide polymorphism Viral diseases Protein Serine-Threonine Kinases Biology Polymorphism Single Nucleotide Microbiology Virus 03 medical and health sciences Genome Analysis Tools In vivo Virology Molecular genetics Genome-Wide Association Studies Genetics [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology medicine Humans MESH: Antibodies Protozoan Genetic Predisposition to Disease [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology 030304 developmental biology Macrophages Host Cells lcsh:R DNA replication Computational Biology HIV Human Genetics MESH: Entamoeba histolytica MESH: Liver Abscess Amebic Viral Replication Viral replication HIV-1 Clinical Immunology lcsh:Q Viral Transmission and Infection 030217 neurology & neurosurgery Genome-Wide Association Study MESH: Antigens Protozoan |
| Zdroj: | PLoS ONE, 6(2):e17190. Public Library of Science Arch Invest Med (Mex) Arch Invest Med (Mex), 2011, 6 (2), pp.e17190. ⟨10.1371/journal.pone.0017190⟩ PLoS ONE, Vol 6, Iss 2, p e17190 (2011) PLoS ONE PLoS ONE, 6(2). Public Library of Science |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0017190 |
| Popis: | International audience; Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages. Methodology/Principal Findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.1661025). While the association was not genome-wide significant (p,161027), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.8461026). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048). Conclusions/Significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo. |
| Databáze: | OpenAIRE |
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