Table 2.

Known Biological Function and Relationship to ASCVD in Significant Proteins

Protein	Biological Function, From STRING	Clinically Relevant Function, From the Literature	Related to CAC	Related to Presence of Plaque
AOC3	Amine oxidase, copper containing 3; membrane primary amine oxidase Cell adhesion protein that participates in lymphocyte extravasation and recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion Has semicarbazide-sensitive (SSAO) monoamine oxidase activity May play a role in adipogenesis	Associated with cardiovascular risk factors	X	X
CCL23	C-C motif chemokine ligand 23	May contribute to vascular inflammation Marker to detect atherosclerosis Has chemotactic properties for monocytes, resting T-lymphocytes, and neutrophils Increased in HIV	X	X
CCL24	C-C motif chemokine 24 Chemotactic for resting T-lymphocytes, and eosinophils Has lower chemotactic activity for neutrophils but none for monocytes and activated lymphocytes Is a strong suppressor of colony formation by a multipotential hematopoietic progenitor cell line Binds to CCR3 Belongs to the intercrine β (chemokine CC) family	Marker of cardiac ageing	X	X
CST3	Cystatin-C As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity Belongs to the cystatin family	Plays pleiotropic roles in human vascular pathophysiology Strong association between circulating cystatin C and risk of future coronary heart disease, ischemic stroke, and heart failure Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (however, this is not thought to be causal)		X
DCN	Decorin May affect the rate of fibrils formation Small leucine rich repeat proteoglycans	Decorin has antifibrotic, anti-inflammation, antioxidant, and antiangiogenic properties	X
GDF-15	Growth differentiation factor 15 Belongs to the TGF-β family	GDF15 associated with incident ASCVD, incident heart failure, all-cause mortality, CVD death While GDF-15 is weakly expressed in most tissues under physiological conditions, its expression may significantly increase in response to cardiovascular inflammation and tissue injury Ischemia, mechanical stretch, neurohormones, and proinflammatory cytokines stimulate the expression of GDF-15 in cardiac myocytes Its prominent antiapoptotic, antihypertrophic, and anti-inflammatory actions in cardiovascular disease models suggest that GDF-15 may play a counter-regulatory role in the context of cardiovascular injury	X	X
IGFBP-7	Insulin-like growth factor-binding protein 7 Binds IGF-I and IGF-II with a relatively low affinity Stimulates prostacyclin (PGI2) production Stimulates cell adhesion I-set domain containing	Marker of CAD	X	X
IL-18BP	Interleukin-18-binding protein Isoform A binds to IL-18 and inhibits its activity Functions as an inhibitor of the early Th1 cytokine response Immunoglobulin-like domain containing	Increased in acute coronary patients	X	X
IL-6RA	Interleukin-6 receptor subunit α Part of the receptor for interleukin 6 Binds to IL-6 with low affinity, but does not transduce a signal Signal activation necessitate an association with IL6ST Activation may lead to the regulation of the immune response, acute-phase reactions, and hematopoiesis CD molecules		X
LTBR	Tumor necrosis factor receptor superfamily member 3 Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT Promotes apoptosis via TRAF3 and TRAF5 May play a role in the development of lymphoid organs Tumor necrosis factor receptor superfamily	Involved in NF-kB signaling pathways		X
MEPE	Matrix extracellular phosphoglycoprotein Promotes renal phosphate excretion and modulates mineralization SIBLING family	Associated with ischemic stroke		X
NCR1	Natural cytotoxicity triggering receptor 1 Cytotoxicity-activating receptor that may contribute to the increased efficiency of activated natural killer (NK) cells to mediate tumor cell lysis		X	X
NRP1	Neuropilin-1 The membrane-bound isoform 1 is a receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits, and in organogenesis outside the nervous system It mediates the chemorepulsant activity of semaphorins It binds to semaphorin 3A, PLGF-2 isoform of PGF, VEGF165 isoform of VEGFA, and VEGFB Coexpression with KDR results in increased VEGF165 binding to KDR as well as increased chemotaxis Regulate VEGF-induced angiogenesis	Role in signaling and angiogenesis	X	X
OSMR	Oncostatin-M-specific receptor subunit β Associates with IL31RA to form the IL-31 receptor Binds IL-31 to activate STAT3 and possibly STAT1 and STAT5 Capable of transducing OSM-specific signaling events Fibronectin type III domain containing	Anti-inflammatory, though to decrease IL-8 mediated recruitment of neutrophils	X
PGF	Placental growth factor; placenta growth factor Growth factor active in angiogenesis and endothelial cell growth, stimulating their proliferation and migration It binds to the receptor FLT1/VEGFR-1 Isoform PlGF-2 binds NRP1/neuropilin-1 and NRP2/neuropilin-2 in a heparin-dependent manner Also promotes cell tumor growth	Chronic source of background vascular inflammation Marker of overall mortality after non-ST segment acute coronary syndrome	X	X
PLC	Basement membrane-specific heparan sulfate proteoglycan core protein Integral component of basement membranes Component of the glomerular basement membrane, responsible for the fixed negative electrostatic membrane charge, and provides a barrier which is both size- and charge-selective It serves as an attachment substrate for cells Plays essential roles in vascularization Critical for normal heart development and for regulating the vascular response to injury Also required for avascular cartilage development I-set domain containing	Regulates inflammation and angiogenesis		X
REG1A	Lithostathine-1-α Might act as an inhibitor of spontaneous calcium carbonate precipitation May be associated with neuronal sprouting in brain, and with brain and pancreas regeneration C-type lectin domain containing		X	X
SERPINA5	Plasma serine protease inhibitor Heparin-dependent serine protease inhibitor acting in body fluids and secretions Inactivates serine proteases by binding irreversibly to their serine activation site Involved in the regulation of intravascular and extravascular proteolytic activities Plays hemostatic roles in the blood plasma Acts as a procoagulant and proinflammatory factor by inhibiting the anticoagulant activated protein C factor as well as the generation of activated protein C factor by the thrombin/thrombomodulin complex			X
ST2	Interleukin-1 receptor-like 1 Receptor for IL-33 Signaling requires association of the coreceptor IL1RAP Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8 Possibly involved in helper T-cell function I-set domain containing	Associated with death, heart failure, MACE (sST2)	X
TNF-R1	Tumor necrosis factor receptor superfamily member 1A Receptor for TNFSF2/TNF-αand homotrimeric TNFSF1/lymphotoxin-α The adapter molecule FADD recruits caspase-8 to the activated receptor The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate- specific cysteine proteases) mediating apoptosis Contributes to the induction of noncytocidal TNF effects including antiviral state and activation of the acid sphingomyelinase CD molecules	Associated with cardiovascular mortality in patients with chronic coronary heart disease	X	X
TNFRSF4	Tumor necrosis factor receptor superfamily member 4 Receptor for TNFSF4/OX40L/GP34 A costimulatory molecule implicated in long-term T-cell immunity CD molecules	Blocking of the TNFRSF4 pathway leads to reducedatherogenesis and a regression of atherosclerosis	X	X
TNFSF13B	Tumor necrosis factor ligand superfamily member 13B Cytokine that binds to TNFRSF13B/TACI and TNFRSF17/BCMA TNFSF13/APRIL binds to the same 2 receptors Together, they form a 2 ligands-2 receptors pathway involved in the stimulation of B- and T-cell function and the regulation of humoral immunity A third B-cell specific BAFF-receptor (BAFFR/BR3) promotes the survival of mature B cells and the B-cell response CD molecules			X
VCAM1	Vascular cell adhesion protein 1 Important in cell-cell recognition Appears to function in leukocyte-endothelial cell adhesion Interacts with integrin α-4/β-1 (ITGA4/ITGB1) on leukocytes, and mediates both adhesion and signal transduction The VCAM1/ITGA4/ITGB1 interaction may play a pathophysiologic role both in immune responses and in leukocyte emigration to sites of inflammation C2-set domain containing	Marker of endothelial dysfuntion, increased in rheumatoid arthritis, associated with plaque and carotid intima-media thickness (CIMT)	X

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CAD, coronary artery disease; CVD, cardiovascular disease; HIV, human immunodeficiency virus; IL, interleukin; MACE, major adverse cardiovascular events; NF-kB, nuclear factor-κB; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.