title: Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins.
abstract: OBJECTIVE
  We previously demonstrated that subjects with functional ATP-binding cassette (ABC) A1 mutations have increased atherosclerosis, which has been attributed to the role of ABCA1 in reverse cholesterol transport. More recently, a proinflammatory effect of Abca1 deficiency was shown in mice, potentially contributing to atherogenesis. In this study, we investigated whether ABCA1 deficiency was associated with proinflammatory changes in humans.
  
  
  RESULTS
  Thirty-one heterozygous, 5 homozygous ABCA1 mutation carriers, and 21 matched controls were studied. (18)Fluorodeoxyglucose positron emission tomography with computed tomographic scanning was performed in a subset of carriers and controls to assess arterial wall inflammation (target:background ratio). Heterozygous ABCA1 mutation carriers had a 20% higher target:background ratio than in controls (target:background ratio; P=0.008). In carriers using statins (n=7), target:background ratio was 21% reduced than in nonstatin users (n=7; P=0.03). We then measured plasma cytokine levels. Tumor necrosis factor α, monocyte chemoattractant protein-1, and interleukin-6 levels were increased in heterozygous and homozygous ABCA1 mutation carriers. We isolated monocytes from carriers and controls and measured inflammatory gene expression. Only TNFα mRNA was increased in monocytes from heterozygous ABCA1 mutation carriers. Additional studies in THP-1 macrophages showed that both ABCA1 deficiency and lipoprotein-deficient plasma from ABCA1 mutation carriers increased inflammatory gene expression.
  
  
  CONCLUSIONS
  Our data suggest a proinflammatory state in ABCA1 mutation carriers as reflected by an increased positron emission tomography-MRI signal in nonstatin using subjects, and increased circulating cytokines. The increased inflammation in ABCA1 mutation carriers seems to be attenuated by statins.
authors.affiliation: From the Department of Vascular Medicine (A.E.B., F.M.v.d.V, E.S.S.) and Department of Medical Biochemistry (M.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.E.B., S.T., M.W., A.R.T.). a.e.bochem@amc.nl.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Bochem
authors.affiliation: From the Department of Vascular Medicine (A.E.B., F.M.v.d.V, E.S.S.) and Department of Medical Biochemistry (M.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.E.B., S.T., M.W., A.R.T.).
authors.forename: Fleur M
authors.initials: FM
authors.lastname: van der Valk
authors.affiliation: From the Department of Vascular Medicine (A.E.B., F.M.v.d.V, E.S.S.) and Department of Medical Biochemistry (M.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.E.B., S.T., M.W., A.R.T.).
authors.forename: Sonia
authors.initials: S
authors.lastname: Tolani
authors.affiliation: From the Department of Vascular Medicine (A.E.B., F.M.v.d.V, E.S.S.) and Department of Medical Biochemistry (M.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.E.B., S.T., M.W., A.R.T.).
authors.forename: Erik S
authors.initials: ES
authors.lastname: Stroes
authors.affiliation: From the Department of Vascular Medicine (A.E.B., F.M.v.d.V, E.S.S.) and Department of Medical Biochemistry (M.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.E.B., S.T., M.W., A.R.T.).
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.affiliation: From the Department of Vascular Medicine (A.E.B., F.M.v.d.V, E.S.S.) and Department of Medical Biochemistry (M.W.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (A.E.B., S.T., M.W., A.R.T.).
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001055:Apolipoproteins B / Q000097:blood; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D009154:Mutation; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control
chemical_list: D018528:ATP-Binding Cassette Transporters; D001055:Apolipoproteins B; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D002784:Cholesterol
keywords: ABCA1; HDL; cytokines; dyslipidemia; genetics; lipids; positron-emission tomography