title: Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes: the Athero-Express Genomics Study.
abstract: BACKGROUND
  The eicosanoid genes ALOX5, ALOX5AP and LTA4H have been implicated in atherosclerosis. We assessed the impact of common variants in these genes on gene expression, circulating protein levels, and atherosclerotic plaque phenotypes.
  
  
  METHODS
  We included patients from the Stockholm Atherosclerosis Gene Expression study (STAGE, N = 109), and the Athero-Express Biobank Study (AE, N = 1443). We tested 1453 single-nucleotide variants (SNVs) in ALOX5, ALOX5AP and LTA4H for association with gene expression in STAGE. We also tested these SNVs for association with seven histologically defined plaque phenotypes in the AE (which included calcification, collagen, cellular content, atheroma size, and intraplaque vessel density and hemorrhage).
  
  
  RESULTS
  We replicate a known cis-eQTL (rs6538697, p = 1.96 × 10(-6)) for LTA4H expression in whole blood of patients from STAGE. We found no significant association for any of the SNVs tested with serum levels of ALOX5 or ALOX5AP (p > 5.79 × 10(-4)). For atherosclerotic plaque phenotypes the strongest associations were found for intraplaque vessel density and smooth muscle cells in the ALOX5AP locus (p > 1.67 × 10(-4)).
  
  
  CONCLUSIONS
  We replicate a known eQTL for LTA4H expression in whole blood using STAGE data. We found no associations of variants in and around ALOX5, ALOX5AP and LTA4H with serum ALOX5 or ALOX5AP levels, or plaque phenotypes. On the supposition that these genes play a causal role in atherosclerosis, these results suggest that common variants in these loci play a limited role (if any) in influencing advanced atherosclerotic plaque morphology to the extent that it impacts atherosclerotic disease.
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands. Electronic address: s.w.vanderlaan-2@umcutrecht.nl.
authors.forename: Sander W
authors.initials: SW
authors.lastname: van der Laan
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hassan
authors.initials: H
authors.lastname: Foroughi Asl
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands.
authors.forename: Pleunie
authors.initials: P
authors.lastname: van den Borne
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: van Setten
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands.
authors.forename: M E Madeleine
authors.initials: ME
authors.lastname: van der Perk
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands.
authors.forename: Sander M
authors.initials: SM
authors.lastname: van de Weg
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands.
authors.forename: Arjan H
authors.initials: AH
authors.lastname: Schoneveld
authors.affiliation: Cardiovascular Research Institute, Singapore, Singapore.
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
authors.affiliation: Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Michoel
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan L M
authors.initials: JL
authors.lastname: Björkegren
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands.
authors.forename: Hester M
authors.initials: HM
authors.lastname: den Ruijter
authors.affiliation: Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Medical Genetics, Center of Molecular Medicine, UMC Utrecht, The Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, UMC Utrecht, The Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht, The Netherlands; Laboratory of Clinical Chemistry and Hematology, Division Laboratories & Pharmacy, UMC Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics*; D000368:Aged; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D050197:Atherosclerosis / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D018070:Biological Specimen Banks; D002340:Carotid Artery Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D005263:Femoral Artery / Q000201:enzymology* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D013548:Sweden
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase
keywords: ALOX5; Atherosclerosis; Eicosanoids; Plaque; Single-nucleotide polymorphism