title: CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation.
abstract: Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1β in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-κB (nuclear factor κB). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1β, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P<0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.
authors.affiliation: Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
authors.forename: Geena Varghese
authors.initials: GV
authors.lastname: Paramel
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.forename: Ali Ateia
authors.initials: AA
authors.lastname: Elmabsout
authors.forename: Eva
authors.initials: E
authors.lastname: Särndahl
authors.forename: Pia
authors.initials: P
authors.lastname: Lundman
authors.forename: Jan-Håkan
authors.initials: JH
authors.lastname: Jansson
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Allan
authors.initials: A
authors.lastname: Sirsjö
authors.forename: Karin
authors.initials: K
authors.lastname: Fransén
mesh_terms: D050197:Atherosclerosis / Q000097:blood / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D018932:Chemokine CCL2 / Q000097:blood; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D018836:Inflammation Mediators / Q000097:blood; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013548:Sweden
chemical_list: D015415:Biomarkers; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D009363:Neoplasm Proteins; D002097:C-Reactive Protein