title: Genetic loci on chromosome 5 are associated with circulating levels of interleukin-5 and eosinophil count in a European population with high risk for cardiovascular disease.
abstract: IL-5 is a Th2 cytokine which activates eosinophils and is suggested to have an atheroprotective role. Genetic variants in the IL5 locus have been associated with increased risk of CAD and ischemic stroke. In this study we aimed to identify genetic variants associated with IL-5 concentrations and apply a Mendelian randomisation approach to assess IL-5 levels for causal effect on intima-media thickness in a European population at high risk of coronary artery disease. We analysed SNPs within robustly associated candidate loci for immune, inflammatory, metabolic and cardiovascular traits. We identified 2 genetic loci for IL-5 levels (chromosome 5, rs56183820, BETA=0.11, P=6.73E(-5) and chromosome 14, rs4902762, BETA=0.12, P=5.76E(-6)) and one for eosinophil count (rs72797327, BETA=-0.10, P=1.41E(-6)). Both chromosome 5 loci were in the vicinity of the IL5 gene, however the association with IL-5 levels failed to replicate in a meta-analysis of 2 independent cohorts (rs56183820, BETA=0.04, P=0.2763, I(2)=24, I(2)-P=0.2516). No significant associations were observed between SNPs associated with IL-5 levels or eosinophil count and IMT measures. Expression quantitative trait analyses indicate effects of the IL-5 and eosinophil-associated SNPs on RAD50 mRNA expression levels (rs12652920 (r2=0.93 with rs56183820) BETA=-0.10, P=8.64E(-6) and rs11739623 (r2=0.96 with rs72797327) BETA=-0.23, P=1.74E(-29), respectively). Our data do not support a role for IL-5 levels and eosinophil count in intima-media thickness, however SNPs associated with IL-5 and eosinophils might influence stability of the atherosclerotic plaque via modulation of RAD50 levels.
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: McLeod
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.affiliation: CTSU - Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Elsa
authors.initials: E
authors.lastname: Valdes-Marquez
authors.affiliation: Experimental Cardiovascular Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: Harry
authors.initials: H
authors.lastname: Björkbacka
authors.affiliation: Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Gertow
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper R
authors.initials: JR
authors.lastname: Gådin
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bäcklund
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Sennblad
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Italy; Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.affiliation: Centre for Cardiovascular Genetics, University College London, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Italy; Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.affiliation: Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.affiliation: Experimental Cardiovascular Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: CTSU - Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Jemma C
authors.initials: JC
authors.lastname: Hopewell
authors.affiliation: CTSU - Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Björck
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Centre for Clinical Research Västerås, Uppsala University, SE-72189 Västerås, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Öhrvik
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
mesh_terms: D017766:Acid Anhydride Hydrolases; D000368:Aged; D059168:Carotid Intima-Media Thickness; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004804:Eosinophils / Q000378:metabolism*; D005060:Europe; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005828:Genetics, Population; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D015848:Interleukin-5 / Q000097:blood / Q000235:genetics*; D007958:Leukocyte Count; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D004268:DNA-Binding Proteins; D015848:Interleukin-5; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes
keywords: Eosinophil count; Genetics; IL-5; Intima-media thickness; RAD50; Subclinical atherosclerosis
references.citation: Diabet Med. 2000 Apr;17(4):299-307
references.pmid: 10821297
references.citation: Cell. 2015 Apr 9;161(2):387-403
references.pmid: 25772697
references.citation: Cell. 1991 Sep 20;66(6):1165-74
references.pmid: 1833064
references.citation: Cell. 1991 Sep 20;66(6):1175-84
references.pmid: 1833065
references.citation: J Intern Med. 1993 Jan;233(1):45-51
references.pmid: 8429286
references.citation: Stroke. 1999 Apr;30(4):841-50
references.pmid: 10187889
references.citation: Lipids. 2005 Dec;40(12):1215-20
references.pmid: 16477805
references.citation: PLoS Genet. 2006 May;2(5):e72
references.pmid: 16710446
references.citation: J Immunol. 2007 Jan 1;178(1):592-604
references.pmid: 17182600
references.citation: Platelets. 2007 Feb;18(1):16-23
references.pmid: 17365849
references.citation: J Am Coll Cardiol. 2007 May 29;49(21):2129-38
references.pmid: 17531663
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Stroke. 2007 Nov;38(11):2873-80
references.pmid: 17901390
references.citation: J Immunol. 2008 Jan 15;180(2):1199-206
references.pmid: 18178860
references.citation: J Leukoc Biol. 2008 Feb;83(2):229-36
references.pmid: 17875811
references.citation: J Am Coll Cardiol. 2008 Oct 21;52(17):1370-8
references.pmid: 18940525
references.citation: Adv Immunol. 2009;101:81-121
references.pmid: 19231593
references.citation: Nat Genet. 2009 Mar;41(3):342-7
references.pmid: 19198610
references.citation: Int Immunol. 2009 Dec;21(12):1303-9
references.pmid: 19819937
references.citation: Eur Heart J. 2010 Mar;31(5):614-22
references.pmid: 19952003
references.citation: Curr Opin Pharmacol. 2010 Apr;10(2):197-202
references.pmid: 20207195
references.citation: JACC Cardiovasc Imaging. 2010 Aug;3(8):806-10
references.pmid: 20705259
references.citation: Circ Cardiovasc Genet. 2010 Aug;3(4):365-73
references.pmid: 20562444
references.citation: PLoS Genet. 2011 Sep;7(9):e1002260
references.pmid: 21966275
references.citation: Nat Genet. 2011 Dec;43(12):1193-201
references.pmid: 22057235
references.citation: J Immunol. 2012 Jan 15;188(2):703-13
references.pmid: 22174445
references.citation: J Allergy Clin Immunol. 2012 Mar;129(3):702-707.e2
references.pmid: 22244598
references.citation: PLoS Genet. 2012;8(8):e1002793
references.pmid: 22876189
references.citation: Nat Genet. 2012 Oct;44(10):1084-9
references.pmid: 22941192
references.citation: J Am Coll Cardiol. 2012 Oct 16;60(16):1489-99
references.pmid: 22999719
references.citation: Nature. 2012 Nov 1;491(7422):119-24
references.pmid: 23128233
references.citation: Circ Cardiovasc Genet. 2012 Dec;5(6):656-65
references.pmid: 23152477
references.citation: Arterioscler Thromb Vasc Biol. 2013 Mar;33(3):637-44
references.pmid: 23307873
references.citation: Nat Genet. 2013 Oct;45(10):1238-43
references.pmid: 24013639
references.citation: Cell. 2013 Sep 26;155(1):242-56
references.pmid: 24074872
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1033-9
references.pmid: 24285297
references.citation: Int J Mol Med. 2014 Apr;33(4):777-83
references.pmid: 24535646
references.citation: Atherosclerosis. 2015 Mar;239(1):125-30
references.pmid: 25587992
references.citation: Lancet. 2015 Jan 10;385(9963):117-71
references.pmid: 25530442
references.citation: Circ Res. 2015 Feb 27;116(5):816-26
references.pmid: 25524056
references.citation: J Clin Invest. 2004 Aug;114(3):427-37
references.pmid: 15286809