TABLE 3.
Evidence supporting association of candidate gene expression, protein, or genotypic variation with atherosclerotic lesion characteristics, systemic pathology related to atherosclerosis, risk factors for CAD, or clinical outcomes in coronary heart disease. Abbreviations: CAD – coronary artery disease, ACS – acute coronary syndrome, MI – myocardial infarction, SMC – smooth muscle cells, VSMC – vascular smooth muscle cells, PBMCs – peripheral blood mononuclear cells.
| Candidate gene | Published evidence for association of candidate gene or gene product with atherosclerosis (selected references) |
|---|---|
| CCR3 | Overexpressed in human atheromaS30 |
| CD28 | Required for T-cell response to plaque antigen(s)S64 |
| CD4 | Lineage marker for the majority of T-cells found in human atheroma (reviewed in S65) |
| CD69 | Higher percentages of T-cells with this marker found in patients with ACS and CAD than controls6 |
| CD86 | Upregulated in dendritic cells derived from CAD patientsS53 |
| CSF2RB | Codes for receptor subunit detected in cultured SMCs and endothelial and SMCs in human atheromataS31 |
| CTLA4 | Increased expression associated with reduced plaque size in HSP60-tolerant LDLr-/- miceS32 |
| FYN | Polymorphisms associated with blood pressureS23 |
| GRB2 | Required for oxLDL uptake by macrophages and for lesion formation in miceS42 |
| HLA-DRA | Expression induced in vascular endothelial cells by interferon-γ via reactive oxygen speciesS49 |
| HLA-DRB1 | Genotype associated with CAD in ACS patients and in transplantation recipientsS25 |
| ICOS | Expressed abundantly in plaques from ApoE-KO miceS33; increase in atherosclerosis in LDLR-/- mice transplanted with ICOS-deficient marrowS43 |
| IFNG | Implicated in reactive oxygen species formation and lesion development (reviewed in S44); transcript levels are increased in the periphery of ACS patients vs. controls4. |
| IL4R | Expressed in atherosclerotic plaques in both Ldlr-/- mice and in humansS34 |
| IL10 | Inhibits LDL-induced IL-12 release, overexpression decreases lesion size and complexity in LDLr-/- mice (19,24; reviewed in S45) |
| IL12B/IL12p40 | Expressed abundantly in human atherosclerotic plaques19-20; expressed in aortas of apoE-deficient mice20; expression in human endothelial cells attenuated via IL-10S50 |
| IL15 | Expressed in human and ApoE-deficient mouse atherosclerotic lesionsS35-S36; co-localized with CD40L-positive T cells in human lesionsS35 |
| IL18 | Present in plasma of patients presenting with myocardial ischemiaS54; circulating levels associated with myocardial infarction and plaque areaS55, and severity of heart failure21 |
| IRF1 | Protein upregulated by TNFα and IFNγ, stimulating pro-atherogenic endothelin-1 release in human VSMCsS47; mediates apoptosis in VSMCs via PPARγS48 |
| ITGB2 | Activation on T cells independently predicts severe CAD and MIS56 |
| LTA/TNFB | Genotype associated with extent of coronary atherosclerosisS26; polymorphism associated with increased intima-media thickness of carotid arteryS27 polymorphisms associated with increased risk of myocardial infarctionS28; present in fatty streak lesions of the aortic sinus, reduced atherosclerosis in LTα -/- mice11 |
| NFATC1 | Mediates injury-induced vascular wall remodelingS66 |
| NFATC3 | Changes in blood glucose are detected by NFATc3 in arterial smooth muscle, upregulating expression of osteopontin, a promoter of vascular diseaseS67 |
| NFKB1 | Implicated in pathways controlling lipid-dependent gene expression and lesion inflammationS68; stimulates upregulation of pro-atherogenic endothelin-1 release from human VSMCsS47; promotor polymorphisms associated with endothelial function in subjects with pre- and stage I hypertensionS24; implicated in inflammatory gene expression and neointima formation following carotid injury in miceS69; increase in NF-κB activation in PBMCs and human carotid lesionsS37 |
| PTPN11/SHP2 | Increased expression and SMC proliferation in rat aorta via pro-atherogenic advanced glycation end-product stimulation of NF-κBS38; part of signaling pathway regulating adhesion molecule expression in endothelial cellsS51 |
| PTPN22 | Polymorphisms associated with carotid artery intima-media thickness and multiple risk factors for atherosclerosis in a Finnish populationS29 |
| STAT1 | Regulates foam cell formation in vitro, and deficiency reduces lesion size in apoe-/- miceS46; stimulates upregulation of pro-atherogenic endothelin-1 from human VSMCsS47 |
| STAT6 | Differentially expressed in coronary arteries from patients with ischemic heart disease, upregulated in VSMCs of the same arteriesS39; expression increases in human lesion-derived cells resistant to apoptosisS40 |
| TNFRSF5/CD40 | Expressed in human fatty streaks and complicated plaquesS41; upregulated in dendritic cells derived from CAD patientsS53 |
| TNFSF6/FASL | Expression in circulating leukocytes associated with endothelial dysfunction in hyperlipidemic patientsS52; implicated in plaque vulnerability in miceS70; overexpressed in PBMCs and human carotid plaquesS37 |
| TNFSF11/RANKL | Baseline serum levels predict CVD risk over a 15-year period in a human study populationS57; increased T cell expression associated with unstable disease (ACS)S58 |
| ZAP-70 | Signal transduction in T-cells via pro-atherogenic lysophosphatidylcholineS71 |