title: The role of chemokine C-C motif ligand 2 genotype and cerebrospinal fluid chemokine C-C motif ligand 2 in neurocognition among HIV-infected patients.
abstract: OBJECTIVE
  We examined interrelationships between chemokine C-C motif ligand 2 (CCL2) genotype and expression of inflammatory markers in the cerebrospinal fluid (CSF), plasma viral load, CD4 cell count and neurocognitive functioning among HIV-infected adults. We hypothesized that HIV-positive carriers of the 'risk' CCL2 -2578G allele, caused by a single nucleotide polymorphism (SNP) at rs1024611, would have a higher concentration of CCL2 in CSF, and that CSF CCL2 would be associated with both higher concentrations of other proinflammatory markers in CSF and worse neurocognitive functioning.
  
  
  METHODS
  A cross-sectional study of 145 HIV-infected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom genotyping, CSF and neurocognitive data were available.
  
  
  METHODS
  Genomic DNA was extracted from peripheral blood mononuclear cells and/or frozen tissue specimens. CSF levels of CCL2, interleukin (IL)-2, IL-6, tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), soluble tumor necrosis factor receptor 2, sIL-6Rα, sIL-2, sCD14 and B-cell activating factor were quantified. Neurocognitive functioning was measured using a comprehensive battery of neuropsychological tests.
  
  
  RESULTS
  Carriers of the CCL2 -2578G allele had a significantly higher concentration of CCL2 in CSF. CSF CCL2 level was positively and significantly associated with other CSF neuroinflammatory markers and worse cognitive functioning. There was a significant association between genotype and plasma viral load, such that carriers of the CCL2 -2578G allele with high viral load expressed greater levels of CCL2 and had higher neurocognitive deficit scores than other genotype/viral load groups.
  
  
  CONCLUSIONS
  Individuals with the CCL2 -2578G allele had higher levels of CCL2 in CSF, which was associated with increased pro-inflammatory markers in CSF and worse neurocognitive functioning. The results highlight the potential role of intermediate phenotypes in studies of genotype and cognition.
authors.affiliation: aDepartment of Psychiatry and Biobehavioral Sciences bDepartment of Family Medicine cDepartment of Obstetrics & Gynecology dDepartment of Epidemiology and Microbiology eDepartment of Immunology & Human Genetics fDepartment of Neurology, University of California, Los Angeles gGreater Los Angeles VA Healthcare System, Los Angeles, California hDepartment of Neurology iDepartment of Pathology jDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York kDepartment of Pathology lDepartment of Neuroscience mDepartment of Cell Biology, University of Texas Medical Branch, Galveston, Texas nDepartment of Psychiatry, University of California, San Diego, California, USA.
authors.forename: April D
authors.initials: AD
authors.lastname: Thames
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Briones
authors.forename: Larry I
authors.initials: LI
authors.lastname: Magpantay
authors.forename: Otoniel
authors.initials: O
authors.lastname: Martinez-Maza
authors.forename: Elyse J
authors.initials: EJ
authors.lastname: Singer
authors.forename: Charles H
authors.initials: CH
authors.lastname: Hinkin
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
authors.forename: Keith
authors.initials: K
authors.lastname: Heizerling
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Levine
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D018791:CD4 Lymphocyte Count; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D018932:Chemokine CCL2 / Q000235:genetics*; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000134:cerebrospinal fluid; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010949:Plasma / Q000821:virology; D019562:Viral Load; D055815:Young Adult
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines