title: Human genetic evidence for involvement of CD137 in atherosclerosis.
abstract: Atherosclerosis is an inflammatory disease and the main cause of cardiovascular disease. Inflammation promotes plaque instability and clinical disease, such as myocardial infarction, stroke and peripheral vascular disease. Subclinical atherosclerosis begins with thickening of the arterial intimal layer, and increased intima-media thickness (IMT) in the carotid artery is a widely used measurement of subclinical atherosclerosis. Activation of CD137 (tumor necrosis factor receptor super family 9) promotes inflammation and disease development in murine atherosclerosis. CD137 is expressed in human atherosclerosis, but its role is largely unknown. This study uses a genetic approach to investigate CD137 in human atherosclerotic disease. In publicly available data on genotype and gene expression from the HapMap project, the minor T allele of rs2453021, a single nucleotide polymorphism in CD137, was significantly associated with CD137 gene expression. In the PROCARDIS and Wellcome Trust Case Control Consortium (WTCCC) cohorts of 13,029 cases and controls, no significant association was detected between the minor T allele of rs2453021 and risk for coronary artery disease or myocardial infarction. However, in the IMPROVE multicenter study of 3,418 individuals, the minor T allele of rs2453021 was associated with increased IMT of the common carotid artery (CCA), as measured by ultrasonography, with presence of plaque in CCA and with increased incidence of adverse noncardiac vascular events. Taken together, this study shows that the minor T allele of rs2453021 is associated with increased IMT in the CCA and increased risk of incident noncardiac vascular events, thus providing the first human genetic evidence for involvement of CD137 in atherosclerosis.
authors.affiliation: Experimental Cardiovascular Research Group, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Department of Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leif Å
authors.initials: LÅ
authors.lastname: Söderström
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Gertow
authors.affiliation: Experimental Cardiovascular Research Group, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Department of Molecular Genetics, Novo Nordisk, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Sabater-Lleal
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Sundman
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sheikine
authors.affiliation: Radcliffe Department of Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Anuj
authors.initials: A
authors.lastname: Goel
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.affiliation: Cardiovascular Genetics, BHF Laboratories, Rayne Building, University College London, London, United Kingdom.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
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: Radcliffe Department of Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Experimental Cardiovascular Research Group, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Experimental Cardiovascular Research Group, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.
authors.forename: Peder S
authors.initials: PS
authors.lastname: Olofsson
mesh_terms: D000368:Aged; D000483:Alleles; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging / Q000473:pathology; D059168:Carotid Intima-Media Thickness; D002460:Cell Line; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9