title: Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages.
abstract: 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.
  
  
  RESULTS
  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 = 2.16 × 10(-5)). While the association was not genome-wide significant (p<1 × 10(-7)), 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 = 4.84 × 10(-6)). 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
  These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.
authors.affiliation: Landsteiner Laboratory, Sanquin Research, Department of Experimental Immunology, and Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sebastiaan M
authors.initials: SM
authors.lastname: Bol
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.forename: Sophie
authors.initials: S
authors.lastname: Limou
authors.forename: Yvonne
authors.initials: Y
authors.lastname: van Remmerden
authors.forename: Cédric
authors.initials: C
authors.lastname: Coulonges
authors.forename: Daniëlle
authors.initials: D
authors.lastname: van Manen
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Herbeck
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: Margit
authors.initials: M
authors.lastname: Sieberer
authors.forename: Jantine G
authors.initials: JG
authors.lastname: Sietzema
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.forename: Jeremy
authors.initials: J
authors.lastname: Martinson
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Zagury
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.forename: Angélique B
authors.initials: AB
authors.lastname: van 't Wout
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015810:Linkage Disequilibrium; D008264:Macrophages / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D014779:Virus Replication / Q000235:genetics*; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases