Supplemental Material

Supplemental Table 1. Protein names and respective Olink® panel sorted in alphabetical order

Protein full name Entry name Olink® Panel*

Uniprot ID**

Angiotensin-converting enzyme 2 ACE2 CVD II Q9BYF1Adenosine Deaminase ADA INF P00813Adisintegrin and metalloproteinase with thrombospondin motifs 13 ADAMTS13 CVD II

Q76LX8ADM ADM CVD II P35318Agouti-related protein AGRP CVD II O00253CD166 antigen ALCAM CVD III Q13740Protein AMBP AMBP CVD II P02760Angiopoietin-1 ANG1 CVD II Q15389Aminopeptidase N APN CVD III P15144Axin-1 AXIN1 INF O15169Tyrosine-protein kinase receptor UFO AXL CVD III P30530Azurocidin AZU1 CVD III P20160Brain-derived neurotrophic factor BDNF INF P23560Beta-nerve growth factor BETANGF INF P01138

Bleomycin hydrolase BLMHYDROLASE CVD III Q13867

Bone morphogenetic protein 6 BMP6 CVD II P22004Natriuretic peptides B BNP CVD II P16860Eukaryotic translation initiation factor 4E-binding protein 1 BP1_4E INF Q13541Carbonic anhydrase 5A, mitochondrial CA5A CVD II P35218Caspase-3 CASP3 CVD III P42574Caspase 8 CASP8 INF Q14790Eotaxin-1 CCL11 INF P51671C-C motif chemokine 15 CCL15 CVD III Q16663C-C motif chemokine 16 CCL16 CVD III O15467C-C motif chemokine 17 CCL17 CVD II Q92583C-C motif chemokine 19 CCL19 INF Q99731C-C motif chemokine 20 CCL20 INF P78556C-C motif chemikine 22 CCL22 CVD III O00626C-C motif chemokine 23 CCL23 INF P55773C-C motif chemokine 24 CCL24 CVD III O00175C-C motif chemokine 25 CCL25 INF O15444C-C motif chemokine 28 CCL28 INF Q9NRJ3C-C motif chemokine 3 CCL3 CVD II P10147C-C motif chemokine 4 CCL4 INF P13236Scavenger receptor cysteine-rich type 1 protein M130 CD163 CVD III Q86VB7Natural killer cell receptor 2B4 CD244 INF Q9BZW8T-cell surface glycoprotein CD4 CD4 CVD II P01730CD40L receptor CD40 INF P25942CD40 ligand CD40L CVD II P29965T-cell surface glycoprotein CD5 CD5 INF P06127T cell surface glycoprotein CD6 CD6 INF P30203SLAM family member 5 CD84 CVD II Q9UIB8Complement component C1q receptor CD93 CVD III Q9NPY3CUB domain-containing protein 1 CDCP1 INF Q9H5V8Cadherin-5 CDH5 CVD III P33151Carcinoembryonic antigenrelated cell adhesion molecule 8 CEACAM8 CVD II P31997Chitinase-3-like protein 1 CHI3L1 CVD III P36222Chitotriosidase-1 CHIT1 CVD III Q13231

Contactin-1 CNTN1 CVD III Q12860Collagen alpha-1(I) chain COL1A1 CVD III P02452Carboxypeptidase A1 CPA1 CVD III P15085Carboxypeptidase B CPB1 CVD III P15086Macrophage colony-stimulating factor 1 CSF1 INF P09603Cystatin D CST5 INF P28325Cystatin-B CSTB CVD III P04080Chymotrypsin C CTRC CVD II Q99895Cathepsin D CTSD CVD III P07339Cathepsin L1 CTSL1 CVD II P07711Cathepsin Z CTSZ CVD III Q9UBR2Fractalkine CX3CL1 INF P78423C-X-C motif chemokine 1 (CVD2) CXCL1 CVD II P09341C-X-C motif chemokine 10 CXCL10 INF P02778C-X-C motif chemokine 11 CXCL11 INF O14625C-X-C motif chemokine 16 CXCL16 CVD III Q9H2A7C-X-C motif chemokine 5 CXCL5 INF P42830C-X-C motif chemokine 6 CXCL6 INF P80162C-X-C motif chemokine 9 CXCL9 INF Q07325Decorin DCN CVD II P075852,4-dienoyl-CoA reductase, mitochondrial DECR1 CVD II Q16698Dickkopf-related protein 1 DKK1 CVD II O94907Azurocidin DLK1 CVD III P80370Delta and Notch-like epidermal growth factor-related receptor DNER INF Q8NFT8Epidermal growth factor receptor EGFR CVD III P00533Protein S100-A12 ENRAGE INF P80511Epithelial cell adhesion molecule EPCAM CVD III P16422Ephrin type-B receptor 4 EPHB4 CVD III P54760Fatty acid-binding protein, intestinal FABP2 CVD II P12104Fatty acid-binding protein, adipocyte FABP4 CVD III P15090Tumor necrosis factor receptor superfamily member 6 FAS CVD III P25445Fibroblast growth factor 19 FGF19 INF O95750Fibroblast growth factor 21 (CVD2) FGF21 CVD II Q9NSA1Fibroblast growth factor 23 (CVD2) FGF23 CVD II Q9GZV9Fibroblast growth factor 5 FGF5 INF P12034Fms-related tyrosine kinase 3 ligand FLT3L INF P49771Follistatin FS CVD II P19883Galectin-3 GAL3 CVD III P17931Galectin-4 GAL4 CVD III P56470Galectin-9 GAL9 CVD II O00182Growth/differentiation factor 15 GDF15 CVD III Q99988Growth/differentiation factor 2 GDF2 CVD II Q9UK05Growth hormone GH CVD II P01241Gastric intrinsic factor GIF CVD II P27352Lactoylglutathione lyase GLO1 CVD II Q04760Granulins GRN CVD III P28799Gastrotropin GT CVD II P51161Hydroxyacid oxidase 1 HAOX1 CVD II Q9UJM8Proheparin-binding EGF-like growth factor HBEGF CVD II Q99075Glial cell line-derived neurotrophic factor HGDNF INF P39905Hepatocyte growth factor HGF INF P14210Heme oxygenase 1 HO1 CVD II P09601Osteoclast-associated immunoglobulin-like receptor HOSCAR CVD II Q8IYS5

Heat shock 27 kDa protein HSP27 CVD II P04792Intercellular adhesion molecule 2 ICAM2 CVD III P13598Alpha-L-iduronidase IDUA CVD II P35475Insulin-like growth factor-binding protein 1 IGFBP1 CVD III P08833Insulin-like Growth Factor-Binding Protein 2 IGFBP2 CVD III P18065Insulin-like growth factor-binding protein 7 IGFBP7 CVD III Q16270Low affinity immunoglobulin gamma Fc region receptor II-b

IGGFCRECEPTORIIB CVD II P31994

Interleukin-10 IL10 INF P22301Interleukin-10 receptor subunit alpha IL10RA INF Q13651Interleukin-10 receptor subunit beta IL10RB INF Q08334Interleukin-12 subunit beta IL12B INF P29460Interleukin-13 IL13 INF P35225Interleukin-15 receptor subunit alpha IL15RA INF Q13261Pro-interleukin-16 IL16 CVD II Q14005Interleukin-17A IL17A INF Q16552Interleukin-17C IL17C INF Q9P0M4Interleukin-17D IL17D CVD II Q8TAD2Interleukin-17 receptor A IL17RA CVD III Q96F46Interleukin-18 (CVD2) IL18 CVD II Q14116Interleukin-18-binding protein IL18BP CVD III O95998Interleukin-18 receptor 1 IL18R1 INF Q13478Interleukin-1 receptor antagonist protein IL1RA CVD II P18510Interleukin-1 receptor-like 2 IL1RL2 CVD II Q9HB29Interleukin-1 receptor type 1 IL1RT1 CVD III P14778Interleukin-1 receptor type 2 IL1RT2 CVD III P27930Interleukin-20 receptor subunit alpha IL20RA INF Q9UHF4Interleukin-27 IL27 CVD II Q8NEV9Interleukin-2 receptor subunit alpha IL2RA CVD III P01589Interleukin-4 receptor subunit alpha IL4RA CVD II P24394Interleukin-6 (CVD2) IL6 CVD II P05231Interleukin-6 receptor subunit alpha IL6RA CVD III P08887Interleukin-7 IL7 INF P13232Interleukin-8 IL8 INF P10145Melusin ITGB1BP2 CVD II Q9UKP3Integrin beta-2 ITGB2 CVD III P05107Junctional adhesion molecule A JAMA CVD III Q9Y624Kidney injury molecule 1 KIM1 CVD II Q96D42Kallikrein-6 KLK6 CVD III Q92876Latency-associated peptide transforming growth factor beta 1

LAPTGFBETA1 INF P01137

Low-density lipoprotein receptor LDLRECEPTOR CVD III P01130

Leptin LEP CVD II P41159Leukemia inhibitory factor receptor LIFR INF P42702Lectin-like oxidized LDL receptor 1 LOX1 CVD II P78380Lipoprotein lipase LPL CVD II P06858Lymphotoxin-beta receptor LTBR CVD III P36941Macrophage receptor MARCO MARCO CVD II Q9UEW3Myoglobin MB CVD III P02144Monocyte chemotactic protein 1 MCP1_CVD3 CVD III P13500Monocyte chemotactic protein 2 MCP2 INF P80075Monocyte chemotactic protein 3 MCP3 INF P80098Monocyte chemotactic protein 4 MCP4 INF Q99616Matrix extracellular phosphoglycoprotein MEPE CVD III Q9NQ76

Tyrosine-protein kinase Mer MERTK CVD II Q12866Matrix metalloproteinase-1 MMP1 INF P03956Matrix metalloproteinase-10 MMP10 INF P09238Matrix metalloproteinase-12 MMP12 CVD II P39900Matrix metalloproteinase-2 MMP2 CVD III P08253Matrix metalloproteinase-3 MMP3 CVD III P08254Matrix metalloproteinase-7 MMP7 CVD II P09237Matrix metalloproteinase-9 MMP9 CVD III P14780Myeloperoxidase MPO CVD III P05164NF-kappa-B essential modulator NEMO CVD II Q9Y6K9Neurogenic locus notch homolog protein 3 NOTCH3 CVD III Q9UM47Neurotrophin-3 NT3 INF P20783N-terminal prohormone brain natriuretic peptide NTPROBNP P16860Osteoprotegerin OPG_CVD3 CVD III O00300Osteopontin OPN CVD III P10451Oncostatin-M OSM INF P13725Plasminogen activator inhibitor 1 PAI CVD III P05121Pappalysin-1 PAPPA CVD II Q13219Proteinase-activated receptor 1 PAR1 CVD II P25116Poly [ADP-ribose] polymerase 1 PARP1 CVD II P09874Proprotein convertase subtilisin/kexin type 9 PCSK9 CVD III Q8NBP7

Platelet-derived growth factor subunit A PDGFSUBUNITA CVD III P04085

Platelet-derived growth factor subunit B PDGFSUBUNITB CVD II P01127

Programmed cell death 1 ligand 1 PDL1 INF Q9NZQ7Programmed cell death 1 ligand 2 PDL2 CVD II Q9BQ51Platelet endothelial cell adhesion molecule PECAM1 CVD III P16284Peptidoglycan recognition protein 1 PGLYRP1 CVD III O75594Elafin PI3 CVD III P19957Polymeric immunoglobulin receptor PIGR CVD II P01833Perlecan PLC CVD III P98160Placenta growth factor PLGF CVD II P49763Paraoxonase (PON 3) PON3 CVD III Q15166Prolargin PRELP CVD II P51888Brother of CDO PROTEINBOC CVD II Q9BWV1Serine protease 27 PRSS27 CVD II Q9BQR3Prostasin PRSS8 CVD II Q16651Myeloblastin PRTN3 CVD III P24158P-selectin glycoprotein ligand 1 PSGL1 CVD II Q14242Pulmonary surfactant-associated protein D PSPD CVD III P35247Pentraxin-related protein PTX3 PTX3 CVD II P26022Receptor for advanced glycosylation end products RAGE CVD II Q15109Retinoic acid receptor responder protein 2 RARRES2 CVD III Q99969Renin REN CVD II P00797Resistin RETN CVD III Q9HD89Stem cell factor (CVD2) SCF CVD II P21583Secretoglobin family 3A member 2 SCGB3A2 CVD III Q96PL1E-selectin SELE CVD III P16581P-selectin SELP CVD III P16109Serpin A12 SERPINA12 CVD II Q8IW75Tyrosine-protein phosphatase non-receptor type substrate 1 SHPS1 CVD III P78324SIR2-like protein 2 SIRT2 INF Q8IXJ6Signaling lymphocytic activation molecule SLAMF1 INF Q13291

SLAM family member 7 SLAMF7 CVD II Q9NQ25Superoxide dismutase [Mn], mitochondrial SOD2 CVD II P04179Sortilin SORT1 CVD II Q99523Spondin-1 SPON1 CVD III Q9HCB6Spondin-2 SPON2 CVD II Q9BUD6Proto-oncogene tyrosine-protein kinase Src SRC CVD II P12931Sulfotransferase 1A1 ST1A1 INF P50225ST2 protein ST2 CVD III Q01638STAM-binding protein STAMPB INF O95630Serine/threonine-protein kinase 4 STK4 CVD II Q13043Tissue factor TF CVD II P13726Trefoil factor 3 TFF3 CVD III Q07654Tissue factor pathway inhibitor TFPI CVD III P10646Transforming growth factor alpha TGFALPHA INF P01135Protein-glutamine gamma-glutamyltransferase 2 TGM2 CVD II P21980Thrombospondin-2 THBS2 CVD II P35442Thrombopoietin THPO CVD II P40225Angiopoietin-1 receptor TIE2 CVD II Q02763Metalloproteinase inhibitor 4 TIMP4 CVD III Q99727Trem-like transcript 2 protein TLT2 CVD III Q5T2D2Thrombomodulin TM CVD II P07204Tumor necrosis factor TNF INF P01375TNF-beta TNFB INF P01374Tumor necrosis factor receptor 1 TNFR1 CVD III P19438Tumor necrosis factor receptor 2 TNFR2 CVD III P20333Tumor necrosis factor receptor superfamily member 10A TNFRSF10A CVD II O00220Tumor necrosis factor receptor superfamily member 10C TNFRSF10C CVD III O14798Tumor necrosis factor receptor superfamily member 11A TNFRSF11A CVD II Q9Y6Q6Tumor necrosis factor receptor superfamily member 13B TNFRSF13B CVD II O14836Tumor necrosis factor receptor superfamily member 14 TNFRSF14 CVD III Q92956Tumor necrosis factor receptor superfamily member 9 TNFRSF9 INF Q07011Tumor necrosis factor ligand superfamily member 13B TNFSF13B CVD III Q9Y275Tumor necrosis factor ligand superfamily member 14 TNFSF14 INF O43557Tissue-type plasminogen activator TPA CVD III P00750Transferrin receptor protein 1 TR CVD III P02786TNF-related apoptosis-inducing ligand TRAIL INF P50591TNF-related apoptosis-inducing ligand receptor 2 TRAILR2 CVD II O14763TNF-related activation-induced cytokine TRANCE INF O14788Tartrate-resistant acid phosphatase type 5 TRAP CVD III P13686Tumor necrosis factor (Ligand) superfamily, member 12 TWEAK INF O43508Urokinase-type plasminogen activator UPA_CVD3 CVD III P00749Urokinase plasminogen activator surface receptor UPAR CVD III Q03405Vascular endothelial growth factor A VEGFA INF P15692Vascular endothelial growth factor D VEGFD CVD II O43915V-set and immunoglobulin domain-containing protein 2 VSIG2 CVD II Q96IQ7von Willebrand factor VWF CVD III P04275Lymphotactin XCL1 CVD II P47992Legend: *CVII: cardiovascular II; CVIII: cardiovascular III; INF: inflammation panels; **UniProt ID from UniProt Knowledgebase

Supplemental Table 2. Odds ratios (OR) and 95% confidence intervals (CI) for all proteins measured in Phase 1A & 1B, adjusted for the matching variables and for clinical risk factors

Protein* Discovery Replication Combined1

OR 95% CI P-value

OR 95% CI P-value

OR 95% CI P-value

P-value21 BNP 1.5

9(1.37,1.84)

<0.0001

1.77

(1.51,2.07)

<0.0001

1.67

(1.50,1.86)

<0.0001

0.322 NTPROBNP 1.7

9(1.49,2.14)

<0.0001

2.06

(1.66,2.54)

<0.0001

1.89

(1.65,2.17)

<0.0001

0.323 TRAILR2 2.7

0(1.86,3.92)

<0.0001

2.65

(1.72,4.07)

<0.0001

2.68

(2.02,3.55)

<0.0001

0.954 GDF15 2.3

4(1.72,3.19)

<0.0001

1.55

(1.15,2.09)

0.0036 1.89

(1.53,2.34)

<0.0001

0.0585 GAL9 2.3

0(1.48,3.58)

0.0002 2.59

(1.61,4.19)

<0.0001

2.43

(1.76,3.36)

<0.0001

0.726 FGF23 1.4

8(1.20,1.81)

0.0002 1.69

(1.30,2.20)

<0.0001

1.55

(1.32,1.83)

<0.0001

0.427 TNFRSF13B 1.5

8(1.21,2.06)

0.0008 2.33

(1.58,3.44)

<0.0001

1.79

(1.43,2.23)

<0.0001

0.108 TNFRSF10A 2.0

1(1.40,2.88)

0.0002 1.98

(1.31,3.01)

0.0013 2.00

(1.52,2.62)

<0.0001

0.97

Protein* Discovery Replication Combined1

OR 95% CI P-value

OR 95% CI P-value

OR 95% CI P-value

P-value29 UPAR 2.2

7(1.61,3.21)

<0.0001

1.38

(1.00,1.92)

0.052 1.75

(1.38,2.22)

<0.0001

0.04210 VEGFD 1.7

5(1.19,2.58)

0.0045 1.98

(1.36,2.89)

0.0004 1.87

(1.42,2.45)

<0.0001

0.6611 SLAMF7 1.4

1(1.13,1.76)

0.0024 2.00

(1.38,2.91)

0.0003 1.55

(1.28,1.87)

<0.0001

0.1112 TNFRSF11A 1.7

2(1.28,2.31)

0.0003 1.53

(1.12,2.11)

0.0085 1.63

(1.32,2.03)

<0.0001

0.6013 OPN 1.8

1(1.36,2.41)

<0.0001

1.36

(1.03,1.79)

0.030 1.56

(1.28,1.91)

<0.0001

0.1614 TWEAK 0.5

8(0.39,0.85)

0.0052 0.58

(0.42,0.80)

0.0008 0.58

(0.45,0.74)

<0.0001

1.0015 CCL16 1.3

7(1.11,1.68)

0.0030 1.55

(1.18,2.02)

0.0015 1.43

(1.21,1.68)

<0.0001

0.4716 CEACAM8 1.4

7(1.18,1.83)

0.0006 1.36

(1.08,1.73)

0.010 1.42

(1.21,1.67)

<0.0001

0.6617 ADM 2.1

2(1.48,3.05)

<0.0001

1.41

(1.02,1.96)

0.039 1.70

(1.33,2.16)

<0.0001

0.1018 TGM2 1.2

2(1.01,1.48)

0.038 1.55

(1.25,1.91)

<0.0001

1.36

(1.18,1.57)

<0.0001

0.1119 CD4 1.6

7(1.18,2.35)

0.0035 1.86

(1.25,2.77)

0.0021 1.75

(1.35,2.27)

<0.0001

0.6820 FABP4 1.5

7(1.25,1.97)

0.0001 1.28

(1.01,1.61)

0.038 1.42

(1.20,1.67)

<0.0001

0.2221 VEGFA 2.2

7(1.59,3.22)

<0.0001

1.27

(0.89,1.80)

0.18 1.69

(1.32,2.17)

<0.0001

0.02322 CSTB 1.8

4(1.43,2.37)

<0.0001

1.16

(0.93,1.44)

0.18 1.41

(1.20,1.66)

<0.0001

0.006323 TFF3 1.5

2(1.23,1.87)

0.0001 1.25

(0.96,1.62)

0.09 1.40

(1.19,1.65)

<0.0001

0.2524 AGRP 1.6

4(1.23,2.20)

0.0009 1.62

(1.08,2.44)

0.019 1.64

(1.29,2.07)

<0.0001

0.9725 IGFBP2 1.5

5(1.21,1.99)

0.0005 1.35

(1.03,1.77)

0.030 1.46

(1.21,1.75)

<0.0001

0.4526 PLGF 1.8

6(1.27,2.72)

0.0014 1.61

(1.11,2.34)

0.013 1.73

(1.32,2.26)

<0.0001

0.6027 IGFBP1 1.4

1(1.19,1.66)

<0.0001

1.14

(0.95,1.37)

0.15 1.28

(1.14,1.45)

<0.0001

0.1028 HGF 2.1

2(1.50,3.01)

<0.0001

1.29

(0.94,1.77)

0.12 1.62

(1.28,2.05)

<0.0001

0.03929 ACE2 1.4

8(1.16,1.89)

0.0014 1.40

(1.06,1.84)

0.017 1.44

(1.20,1.73)

<0.0001

0.7530 LOX1 1.3

6(1.07,1.74)

0.013 1.46

(1.15,1.86)

0.0018 1.41

(1.19,1.68)

<0.0001

0.6831 ENRAGE 1.2

3(1.04,1.46)

0.014 1.44

(1.15,1.81)

0.0016 1.30

(1.14,1.49)

0.0001 0.2732 SPON1 2.0

5(1.40,2.98)

0.0002 1.42

(0.91,2.21)

0.12 1.75

(1.32,2.34)

0.0001 0.2233 RARRES2 2.4

5(1.42,4.23)

0.0014 1.67

(1.09,2.56)

0.018 1.93

(1.38,2.71)

0.0001 0.2834 CXCL11 1.3

3(1.15,1.54)

0.0001 1.13

(0.96,1.32)

0.14 1.23

(1.11,1.37)

0.0002 0.1335 MMP12 1.4

2(1.13,1.79)

0.0023 1.33

(1.04,1.70)

0.024 1.38

(1.17,1.63)

0.0002 0.6836 SPON2 2.6

6(1.36,5.21)

0.0044 2.10

(1.16,3.79)

0.014 2.33

(1.49,3.63)

0.0002 0.6137 PAR1 1.6

4(1.16,2.31)

0.0048 1.53

(1.07,2.19)

0.019 1.59

(1.24,2.03)

0.0002 0.7938 IL6 1.4

2(1.20,1.68)

<0.0001

1.09

(0.92,1.30)

0.33 1.25

(1.11,1.41)

0.0003 0.03139 KIM1 1.2

9(1.07,1.55)

0.0065 1.31

(1.05,1.62)

0.016 1.30

(1.13,1.49)

0.0003 0.9240 OPG_CVD3 2.0

5(1.42,2.95)

0.0001 1.25

(0.86,1.82)

0.24 1.61

(1.24,2.10)

0.0003 0.06641 TNFR2 1.7

5(1.27,2.42)

0.0007 1.29

(0.98,1.71)

0.074 1.47

(1.19,1.82)

0.0003 0.1642 IL27 1.5

7(1.10,2.26)

0.014 1.77

(1.15,2.72)

0.010 1.65

(1.25,2.18)

0.0004 0.6843 IL2RA 1.6

6(1.25,2.22)

0.0005 1.26

(0.94,1.67)

0.12 1.44

(1.18,1.77)

0.0004 0.1844 TNFR1 1.9

8(1.38,2.84)

0.0002 1.26

(0.92,1.73)

0.15 1.54

(1.21,1.95)

0.0004 0.06645 SORT1 1.9

9(1.17,3.38)

0.011 1.80

(1.12,2.89)

0.015 1.88

(1.32,2.68)

0.0004 0.7846 REN 1.1

8(0.98,1.41)

0.077 1.38

(1.13,1.68)

0.0014 1.27

(1.11,1.45)

0.0005 0.2447 PSPD 1.2

7(1.05,1.54)

0.012 1.32

(1.05,1.67)

0.019 1.29

(1.12,1.49)

0.0006 0.8148 RETN 1.5

8(1.21,2.06)

0.0008 1.22

(0.92,1.62)

0.16 1.40

(1.15,1.69)

0.0007 0.2049 PDL2 1.6

8(1.13,2.50)

0.011 1.62

(1.05,2.50)

0.029 1.65

(1.23,2.22)

0.0008 0.9150 TNFRSF14 1.7

6(1.26,2.46)

0.0009 1.26

(0.93,1.71)

0.14 1.47

(1.17,1.84)

0.0009 0.1551 IL1RA 1.3

7(1.11,1.69)

0.0030 1.17

(0.99,1.39)

0.059 1.25

(1.10,1.42)

0.0009 0.2652 MCP3 1.6

1(1.27,2.05)

<0.0001

1.08

(0.81,1.44)

0.62 1.37

(1.14,1.65)

0.0009 0.03653 IL16 1.3

8(1.06,1.79)

0.016 1.34

(1.04,1.72)

0.023 1.36

(1.13,1.63)

0.0009 0.8754 CASP8 1.2

2(1.04,1.43)

0.013 1.18

(1.02,1.37)

0.029 1.20

(1.08,1.33)

0.0010 0.7555 CXCL9 1.5

2(1.25,1.84)

<0.0001

1.03

(0.83,1.28)

0.79 1.27

(1.10,1.47)

0.0011 0.00956 IL4RA 1.4

2(1.06,1.90)

0.017 1.45

(1.03,2.03)

0.031 1.43

(1.15,1.78)

0.0013 0.9357 IGFBP7 1.4

2(1.04,1.94)

0.026 1.42

(1.05,1.91)

0.021 1.42

(1.15,1.76)

0.0013 0.9958 HSP27 2.0

3(1.32,3.14)

0.0013 1.27

(0.97,1.68)

0.083 1.46

(1.16,1.83)

0.0015 0.07459 MMP2 1.5

5(1.11,2.16)

0.010 1.38

(0.99,1.91)

0.055 1.46

(1.16,1.84)

0.0015 0.6360 TGFALPHA 1.6

6(1.21,2.28)

0.0016 1.23

(0.94,1.61)

0.13 1.39

(1.14,1.71)

0.0015 0.1561 PGLYRP1 1.5

3(1.17,1.98)

0.0016 1.20

(0.92,1.56)

0.19 1.35

(1.12,1.63)

0.0015 0.2062 SLAMF1 1.2

7(1.02,1.58)

0.029 1.42

(1.06,1.89)

0.017 1.32

(1.11,1.57)

0.0015 0.5663 PLC 1.7

7(1.17,2.68)

0.0071 1.43

(0.97,2.11)

0.069 1.58

(1.19,2.10)

0.0015 0.4664 GAL4 1.5

7(1.19,2.05)

0.0012 1.18

(0.89,1.57)

0.26 1.37

(1.13,1.67)

0.0017 0.1665 CD40 1.9

3(1.41,2.66)

<0.0001

1.05

(0.76,1.46)

0.77 1.44

(1.14,1.81)

0.0018 0.008966 IL15RA 1.7

4(1.18,2.56)

0.0053 1.46

(0.86,2.49)

0.16 1.64

(1.20,2.24)

0.0020 0.6167 PON3 0.8

3(0.66,1.04)

0.10 0.72

(0.56,0.91)

0.0064 0.77

(0.66,0.91)

0.0021 0.39

Protein* Discovery Replication Combined1

OR 95% CI P-value

OR 95% CI P-value

OR 95% CI P-value

P-value268 TNFRSF9 1.4

1(1.13,1.76)

0.0025 1.15

(0.86,1.53)

0.34 1.31

(1.10,1.56)

0.0029 0.2769 CCL11 1.4

1(1.05,1.91)

0.024 1.36

(0.97,1.91)

0.073 1.39

(1.11,1.74)

0.0041 0.8770 HOSCAR 1.9

3(1.09,3.39)

0.023 1.68

(0.95,2.97)

0.076 1.80

(1.20,2.69)

0.0042 0.7371 VWF 1.1

5(1.00,1.32)

0.054 1.17

(1.01,1.35)

0.035 1.16

(1.05,1.28)

0.0043 0.8772 LTBR 1.7

0(1.18,2.45)

0.0040 1.22

(0.88,1.68)

0.23 1.41

(1.11,1.79)

0.0050 0.1773 CCL17 1.1

2(0.97,1.29)

0.13 1.22

(1.04,1.42)

0.013 1.16

(1.05,1.29)

0.0050 0.4474 SOD2 2.3

0(1.20,4.42)

0.012 1.53

(0.88,2.66)

0.14 1.81

(1.19,2.77)

0.0057 0.3575 MERTK 1.6

0(1.12,2.28)

0.010 1.29

(0.87,1.91)

0.20 1.45

(1.11,1.89)

0.0058 0.4376 VSIG2 1.2

4(0.96,1.59)

0.10 1.46

(1.06,2.01)

0.020 1.32

(1.08,1.61)

0.0060 0.4377 IL18 1.1

6(0.97,1.41)

0.11 1.24

(1.03,1.49)

0.024 1.20

(1.05,1.37)

0.0064 0.6678 PAPPA 1.2

8(1.00,1.65)

0.054 1.32

(0.99,1.75)

0.058 1.30

(1.07,1.57)

0.0069 0.8979 PTX3 1.2

4(0.97,1.59)

0.082 1.43

(1.03,1.97)

0.030 1.31

(1.08,1.59)

0.0069 0.5080 ST2 1.2

5(0.97,1.62)

0.086 1.33

(1.01,1.76)

0.039 1.29

(1.07,1.56)

0.0078 0.7581 LAPTGFBETA1 1.5

8(1.18,2.12)

0.0021 1.11

(0.84,1.47)

0.47 1.31

(1.07,1.61)

0.0080 0.08482 FAS 1.4

9(1.06,2.09)

0.022 1.29

(0.90,1.84)

0.16 1.39

(1.09,1.78)

0.0088 0.5783 DNER 0.8

5(0.58,1.25)

0.41 0.43

(0.26,0.72)

0.0012 0.67

(0.49,0.91)

0.010 0.03684 PRTN3 1.3

0(1.04,1.64)

0.024 1.18

(0.92,1.51)

0.19 1.24

(1.05,1.47)

0.011 0.5685 THBS2 1.1

1(0.67,1.83)

0.69 2.33

(1.39,3.90)

0.0013 1.59

(1.11,2.28)

0.011 0.04486 DKK1 1.2

7(0.99,1.63)

0.058 1.21

(0.97,1.51)

0.09 1.24

(1.05,1.46)

0.012 0.7687 TIMP4 1.5

4(1.17,2.04)

0.0024 1.08

(0.83,1.41)

0.55 1.28

(1.06,1.55)

0.012 0.07188 CCL23 1.7

4(1.28,2.37)

0.0005 0.98

(0.70,1.37)

0.91 1.33

(1.06,1.67)

0.013 0.01489 IL18BP 1.5

0(1.09,2.07)

0.013 1.18

(0.87,1.59)

0.28 1.32

(1.06,1.64)

0.013 0.2890 CHI3L1 1.2

5(1.06,1.47)

0.0086 1.08

(0.90,1.29)

0.43 1.17

(1.03,1.32)

0.013 0.2491 PRELP 1.3

6(0.74,2.49)

0.32 2.79

(1.31,5.94)

0.0080 1.80

(1.12,2.88)

0.015 0.1592 BP1_4E 1.1

4(1.00,1.30)

0.054 1.12

(0.97,1.29)

0.13 1.13

(1.02,1.25)

0.015 0.8593 HBEGF 1.2

5(0.90,1.75)

0.18 1.34

(1.01,1.77)

0.040 1.30

(1.05,1.61)

0.015 0.7694 EPHB4 1.6

2(1.11,2.37)

0.012 1.19

(0.84,1.69)

0.33 1.37

(1.06,1.77)

0.016 0.2495 CTSL1 1.5

1(1.03,2.20)

0.033 1.26

(0.90,1.76)

0.18 1.36

(1.06,1.75)

0.016 0.4896 IL12B 1.3

0(1.05,1.62)

0.017 1.12

(0.88,1.43)

0.35 1.22

(1.04,1.43)

0.017 0.3797 MCP2 1.3

5(1.07,1.71)

0.013 1.11

(0.88,1.41)

0.37 1.22

(1.04,1.45)

0.017 0.2598 PIGR 1.6

0(0.82,3.13)

0.17 1.90

(1.01,3.57)

0.048 1.75

(1.10,2.77)

0.017 0.7299 GT 1.1

9(0.97,1.44)

0.088 1.26

(0.96,1.65)

0.09 1.21

(1.03,1.42)

0.018 0.72100

AMBP 1.63

(0.85,3.12)

0.14 1.86

(0.97,3.53)

0.060 1.74

(1.10,2.75)

0.018 0.78101

OSM 1.18

(0.99,1.41)

0.064 1.14

(0.96,1.36)

0.13 1.16

(1.03,1.31)

0.018 0.79102

IL6RA 1.58

(1.10,2.25)

0.013 1.17

(0.85,1.61)

0.35 1.33

(1.05,1.70)

0.018 0.22103

ICAM2 1.73

(1.22,2.44)

0.0019 1.06

(0.77,1.45)

0.72 1.32

(1.05,1.67)

0.018 0.041104

TM 1.63

(1.07,2.48)

0.023 1.24

(0.85,1.82)

0.26 1.40

(1.06,1.86)

0.019 0.35105

CXCL10 1.26

(1.05,1.51)

0.012 1.08

(0.89,1.29)

0.44 1.17

(1.03,1.33)

0.019 0.23106

TR 1.29

(1.04,1.61)

0.020 1.12

(0.88,1.43)

0.36 1.21

(1.03,1.43)

0.019 0.39107

TNFSF14 1.22

(0.98,1.52)

0.079 1.17

(0.96,1.44)

0.12 1.19

(1.03,1.39)

0.020 0.81108

CD93 1.38

(0.91,2.09)

0.13 1.44

(0.96,2.15)

0.079 1.41

(1.05,1.88)

0.020 0.90109

MMP9 1.11

(0.95,1.31)

0.19 1.18

(1.00,1.39)

0.048 1.15

(1.02,1.29)

0.021 0.62110

PARP1 1.10

(0.95,1.27)

0.20 1.19

(1.00,1.40)

0.044 1.13

(1.02,1.27)

0.023 0.48111

CCL15 1.29

(1.00,1.65)

0.046 1.18

(0.89,1.57)

0.24 1.24

(1.03,1.49)

0.023 0.67112

MMP3 1.37

(1.09,1.73)

0.0062 1.05

(0.83,1.33)

0.67 1.21

(1.03,1.42)

0.024 0.11113

JAMA 1.29

(1.06,1.58)

0.012 1.07

(0.90,1.28)

0.45 1.17

(1.02,1.33)

0.025 0.17114

FABP2 1.20

(0.97,1.50)

0.10 1.19

(0.95,1.49)

0.14 1.20

(1.02,1.40)

0.026 0.95115

XCL1 1.18

(0.94,1.49)

0.16 1.26

(0.97,1.64)

0.081 1.22

(1.02,1.45)

0.027 0.71116

FS 1.24

(0.88,1.73)

0.22 1.37

(0.98,1.91)

0.064 1.30

(1.03,1.65)

0.029 0.67117

CXCL16 1.66

(1.13,2.46)

0.010 1.12

(0.78,1.60)

0.55 1.34

(1.03,1.74)

0.029 0.14118

PRSS8 1.39

(0.93,2.07)

0.11 1.21

(0.96,1.53)

0.11 1.25

(1.02,1.53)

0.029 0.56119

CSF1 1.91

(1.18,3.09)

0.0088 1.05

(0.57,1.93)

0.87 1.51

(1.04,2.21)

0.031 0.13120

DECR1 1.17

(1.04,1.31)

0.0085 1.02

(0.91,1.15)

0.70 1.09

(1.01,1.19)

0.033 0.11121

MCP1_CVD3 1.23

(1.02,1.49)

0.031 1.09

(0.86,1.38)

0.47 1.18

(1.01,1.36)

0.033 0.43122

CD40L 1.09

(0.97,1.23)

0.13 1.09

(0.97,1.23)

0.14 1.09

(1.01,1.19)

0.034 1.00123

NEMO 1.16

(1.02,1.31)

0.022 1.04

(0.90,1.21)

0.58 1.11

(1.01,1.22)

0.036 0.29124

IL8 1.18

(1.00,1.39)

0.051 1.10

(0.90,1.33)

0.36 1.14

(1.01,1.30)

0.037 0.57125

CCL19 1.08

(0.93,1.26)

0.32 1.21

(1.01,1.45)

0.041 1.13

(1.01,1.27)

0.038 0.36126

GRN 1.66

(1.07,2.57)

0.024 1.16

(0.76,1.75)

0.49 1.37

(1.01,1.85)

0.040 0.24

Protein* Discovery Replication Combined1

OR 95% CI P-value

OR 95% CI P-value

OR 95% CI P-value

P-value212

7PDGFSUBUNITB 1.1

3(0.99,1.29)

0.076 1.09

(0.93,1.28)

0.29 1.11

(1.00,1.23)

0.041 0.76128

IL17D 1.37

(0.96,1.95)

0.082 1.28

(0.80,2.03)

0.31 1.33

(1.01,1.77)

0.045 0.81129

SELP 1.26

(1.00,1.60)

0.053 1.11

(0.89,1.39)

0.36 1.18

(1.00,1.39)

0.046 0.44130

PROTEINBOC 1.17

(0.81,1.71)

0.40 1.59

(1.02,2.48)

0.040 1.33

(1.00,1.77)

0.050 0.30131

MPO 1.36

(1.03,1.79)

0.032 1.09

(0.83,1.43)

0.52 1.21

(1.00,1.48)

0.051 0.28132

CCL20 1.17

(1.02,1.33)

0.022 1.03

(0.90,1.18)

0.69 1.10

(1.00,1.21)

0.055 0.19133

IGGFCRECEPTORIIB

1.25

(0.98,1.58)

0.067 1.13

(0.81,1.57)

0.47 1.21

(1.00,1.46)

0.056 0.63134

GAL3 1.44

(1.08,1.92)

0.012 1.02

(0.76,1.37)

0.89 1.22

(0.99,1.50)

0.058 0.10135

CTSZ 1.44

(1.03,2.02)

0.032 1.09

(0.79,1.52)

0.59 1.25

(0.99,1.58)

0.060 0.25136

TRANCE 0.89

(0.70,1.12)

0.31 0.78

(0.59,1.04)

0.086 0.84

(0.70,1.01)

0.060 0.51137

MMP7 1.12

(0.95,1.32)

0.19 1.10

(0.96,1.26)

0.18 1.11

(0.99,1.23)

0.063 0.88138

PDL1 1.47

(1.09,1.98)

0.011 0.96

(0.67,1.39)

0.85 1.24

(0.99,1.57)

0.063 0.078139

TRAIL 1.12

(0.77,1.64)

0.56 0.42

(0.26,0.67)

0.0003 0.76

(0.56,1.02)

0.067 0.001414

0CNTN1 0.8

6(0.62,1.19)

0.36 0.76

(0.54,1.05)

0.10 0.81

(0.64,1.02)

0.071 0.60141

SIRT2 1.11

(1.00,1.22)

0.049 1.03

(0.92,1.15)

0.64 1.07

(0.99,1.16)

0.072 0.35142

TF 1.24

(0.86,1.78)

0.25 1.35

(0.89,2.05)

0.16 1.29

(0.98,1.69)

0.073 0.76143

PECAM1 1.41

(1.04,1.91)

0.027 1.06

(0.81,1.38)

0.69 1.20

(0.98,1.47)

0.077 0.16144

RAGE 1.20

(0.85,1.68)

0.30 1.31

(0.91,1.88)

0.15 1.25

(0.97,1.60)

0.083 0.73145

CD84 1.28

(0.93,1.77)

0.13 1.17

(0.83,1.66)

0.37 1.23

(0.97,1.56)

0.085 0.71146

IL17C 1.29

(1.01,1.65)

0.040 1.02

(0.75,1.39)

0.88 1.18

(0.98,1.43)

0.088 0.25147

STK4 1.10

(0.98,1.24)

0.09 1.04

(0.92,1.18)

0.50 1.08

(0.99,1.17)

0.089 0.52148

TLT2 1.39

(1.06,1.82)

0.017 0.98

(0.73,1.32)

0.90 1.19

(0.97,1.45)

0.09 0.090149

MMP1 1.10

(0.97,1.24)

0.13 1.06

(0.92,1.22)

0.40 1.08

(0.99,1.19)

0.09 0.72150

CASP3 1.12

(1.00,1.26)

0.049 1.02

(0.90,1.16)

0.75 1.07

(0.99,1.17)

0.09 0.28151

FGF21 1.08

(0.96,1.21)

0.21 1.07

(0.95,1.22)

0.27 1.08

(0.99,1.17)

0.10 0.96152

BMP6 1.17

(0.97,1.42)

0.11 1.08

(0.88,1.31)

0.47 1.12

(0.98,1.29)

0.10 0.55153

DCN 1.15

(0.79,1.67)

0.47 1.33

(0.93,1.91)

0.12 1.24

(0.95,1.61)

0.11 0.58154

PSGL1 1.12

(0.84,1.48)

0.45 1.48

(0.95,2.30)

0.079 1.21

(0.96,1.54)

0.11 0.29155

ANG1 1.09

(0.95,1.25)

0.24 1.08

(0.93,1.26)

0.30 1.08

(0.98,1.20)

0.12 0.96156

CD163 1.35

(1.05,1.75)

0.020 0.99

(0.77,1.27)

0.92 1.15

(0.96,1.38)

0.12 0.083157

SRC 1.15

(0.99,1.35)

0.073 1.03

(0.87,1.21)

0.77 1.09

(0.97,1.22)

0.13 0.31158

IL10RB 1.56

(1.06,2.30)

0.025 0.92

(0.58,1.46)

0.73 1.25

(0.93,1.69)

0.14 0.087159

ST1A1 1.13

(1.00,1.27)

0.059 1.01

(0.89,1.15)

0.89 1.07

(0.98,1.17)

0.14 0.23160

BETANGF 1.38

(0.95,2.00)

0.09 1.06

(0.70,1.62)

0.77 1.23

(0.93,1.62)

0.15 0.37161

IL10 1.31

(1.05,1.63)

0.016 0.96

(0.78,1.20)

0.74 1.12

(0.96,1.31)

0.15 0.051162

PDGFSUBUNITA 1.11

(0.95,1.31)

0.19 1.06

(0.91,1.23)

0.48 1.08

(0.97,1.21)

0.16 0.65163

CXCL6 1.18

(0.99,1.40)

0.068 1.01

(0.84,1.21)

0.90 1.09

(0.96,1.24)

0.16 0.24164

ITGB1BP2 1.09

(0.99,1.19)

0.084 1.01

(0.90,1.12)

0.91 1.05

(0.98,1.13)

0.17 0.30165

EGFR 0.83

(0.53,1.31)

0.43 0.80

(0.55,1.18)

0.26 0.82

(0.61,1.09)

0.17 0.90166

IL1RT1 1.39

(0.94,2.06)

0.10 1.07

(0.76,1.49)

0.70 1.19

(0.93,1.54)

0.17 0.32167

HO1 1.41

(0.99,2.01)

0.059 1.01

(0.71,1.43)

0.96 1.19

(0.93,1.52)

0.18 0.19168

SELE 1.13

(0.85,1.51)

0.41 1.18

(0.87,1.60)

0.29 1.15

(0.93,1.42)

0.19 0.84169

CX3CL1 1.30

(0.96,1.77)

0.09 1.01

(0.72,1.41)

0.96 1.16

(0.92,1.45)

0.20 0.27170

CPB1 1.10

(0.90,1.34)

0.35 1.10

(0.89,1.36)

0.40 1.10

(0.95,1.27)

0.21 0.98171

TNFSF13B 1.35

(0.94,1.94)

0.10 1.04

(0.75,1.44)

0.83 1.17

(0.92,1.49)

0.21 0.29172

MEPE 0.95

(0.72,1.26)

0.72 0.80

(0.60,1.08)

0.15 0.88

(0.72,1.08)

0.21 0.43173

BDNF 1.01

(0.96,1.05)

0.83 1.05

(0.99,1.11)

0.09 1.02

(0.99,1.06)

0.21 0.26174

ADAMTS13 1.08

(0.57,2.04)

0.81 1.61

(0.86,3.03)

0.13 1.32

(0.85,2.07)

0.22 0.38175

STAMPB 1.11

(0.97,1.26)

0.12 1.00

(0.86,1.18)

0.95 1.06

(0.96,1.18)

0.22 0.34176

LIFR 1.44

(0.97,2.14)

0.068 0.94

(0.60,1.49)

0.80 1.20

(0.89,1.62)

0.22 0.17177

THPO 1.18

(0.86,1.63)

0.30 1.11

(0.80,1.56)

0.52 1.15

(0.91,1.45)

0.23 0.80178

HAOX1 1.01

(0.89,1.14)

0.92 0.87

(0.76,1.00)

0.057 0.95

(0.86,1.04)

0.24 0.13179

TRAP 0.98

(0.71,1.35)

0.89 0.80

(0.60,1.08)

0.14 0.88

(0.71,1.09)

0.24 0.38180

ALCAM 1.33

(0.92,1.92)

0.13 1.03

(0.73,1.46)

0.88 1.16

(0.90,1.50)

0.24 0.32181

CCL25 1.35

(1.04,1.75)

0.023 0.85

(0.62,1.17)

0.32 1.12

(0.92,1.37)

0.25 0.028182

ITGB2 1.31

(0.95,1.81)

0.10 1.01

(0.77,1.33)

0.92 1.13

(0.92,1.39)

0.26 0.23183

AXIN1 1.13

(1.01,1.26)

0.040 0.94

(0.81,1.09)

0.41 1.05

(0.96,1.15)

0.26 0.057184

NT3 1.29

(0.96,1.74)

0.09 1.00

(0.76,1.30)

0.99 1.12

(0.92,1.37)

0.27 0.21185

TIE2 1.07

(0.72,1.61)

0.73 1.35

(0.85,2.14)

0.20 1.19

(0.88,1.61)

0.27 0.46

Protein* Discovery Replication Combined1

OR 95% CI P-value

OR 95% CI P-value

OR 95% CI P-value

P-value218

6UPA_CVD3 1.2

0(0.88,1.63)

0.25 1.06

(0.74,1.53)

0.73 1.14

(0.90,1.44)

0.27 0.63187

GH 0.99

(0.90,1.09)

0.87 1.10

(0.99,1.23)

0.067 1.04

(0.97,1.12)

0.28 0.14188

KLK6 0.99

(0.71,1.38)

0.96 0.82

(0.62,1.09)

0.17 0.89

(0.72,1.10)

0.28 0.40189

PI3 1.08

(0.87,1.35)

0.50 1.09

(0.90,1.32)

0.40 1.08

(0.94,1.25)

0.28 0.96190

NOTCH3 1.17

(0.85,1.61)

0.34 1.10

(0.80,1.51)

0.57 1.13

(0.90,1.42)

0.28 0.78191

LDLRECEPTOR 0.97

(0.78,1.20)

0.76 0.85

(0.66,1.09)

0.20 0.91

(0.77,1.08)

0.28 0.44192

CHIT1 1.08

(0.96,1.20)

0.19 1.01

(0.90,1.13)

0.87 1.04

(0.96,1.13)

0.29 0.42193

TNFRSF10C 1.09

(0.83,1.45)

0.53 1.12

(0.85,1.48)

0.41 1.11

(0.91,1.35)

0.30 0.90194

IL7 1.19

(0.98,1.45)

0.086 0.96

(0.78,1.19)

0.73 1.08

(0.93,1.25)

0.31 0.15195

DLK1 0.88

(0.71,1.11)

0.28 0.96

(0.75,1.25)

0.78 0.92

(0.78,1.09)

0.32 0.62196

AZU1 1.06

(0.85,1.34)

0.60 1.07

(0.90,1.26)

0.45 1.07

(0.93,1.22)

0.36 0.97197

SHPS1 1.14

(0.83,1.58)

0.42 1.07

(0.81,1.42)

0.61 1.10

(0.89,1.36)

0.36 0.78198

AXL 1.15

(0.82,1.62)

0.41 1.08

(0.79,1.48)

0.63 1.11

(0.88,1.40)

0.36 0.79199

CCL28 1.11

(0.82,1.51)

0.50 1.09

(0.83,1.44)

0.53 1.10

(0.90,1.35)

0.36 0.94200

BLMHYDROLASE 1.50

(1.08,2.09)

0.015 0.83

(0.60,1.15)

0.26 1.11

(0.88,1.40)

0.37 0.012201

EPCAM 0.96

(0.84,1.11)

0.61 0.94

(0.79,1.11)

0.44 0.95

(0.86,1.06)

0.38 0.79202

COL1A1 1.11

(0.81,1.54)

0.51 1.10

(0.78,1.56)

0.58 1.11

(0.88,1.40)

0.39 0.97203

PCSK9 1.32

(0.97,1.79)

0.079 0.91

(0.66,1.25)

0.55 1.10

(0.88,1.38)

0.39 0.10204

TNFB 0.98

(0.73,1.32)

0.90 0.84

(0.61,1.14)

0.26 0.91

(0.74,1.13)

0.39 0.46205

IL10RA 1.12

(0.76,1.63)

0.57 1.30

(0.65,2.60)

0.46 1.16

(0.83,1.61)

0.39 0.71206

CD5 1.11

(0.84,1.48)

0.46 1.08

(0.75,1.55)

0.68 1.10

(0.88,1.37)

0.40 0.90207

MB 1.02

(0.80,1.30)

0.89 0.85

(0.66,1.09)

0.19 0.93

(0.78,1.11)

0.41 0.31208

CDCP1 1.26

(1.01,1.59)

0.043 0.85

(0.65,1.11)

0.24 1.07

(0.90,1.28)

0.43 0.028209

SCGB3A2 1.09

(0.94,1.27)

0.25 0.99

(0.83,1.17)

0.86 1.04

(0.93,1.17)

0.45 0.38210

IL17A 1.18

(0.91,1.53)

0.22 0.94

(0.67,1.33)

0.73 1.08

(0.88,1.34)

0.45 0.31211

CCL3 1.05

(0.90,1.22)

0.53 1.05

(0.84,1.30)

0.68 1.05

(0.93,1.19)

0.45 0.99212

CCL4 1.14

(0.94,1.39)

0.17 0.96

(0.78,1.18)

0.72 1.06

(0.92,1.22)

0.45 0.23213

APN 1.37

(0.92,2.04)

0.12 0.92

(0.64,1.32)

0.66 1.10

(0.85,1.44)

0.46 0.15214

IDUA 1.25

(0.95,1.64)

0.11 0.94

(0.74,1.21)

0.64 1.07

(0.89,1.29)

0.46 0.13215

GLO1 1.05

(0.86,1.27)

0.64 1.07

(0.85,1.34)

0.57 1.06

(0.91,1.22)

0.47 0.90216

GDF2 1.03

(0.83,1.27)

0.81 1.10

(0.87,1.40)

0.42 1.06

(0.90,1.24)

0.48 0.66217

IL18R1 1.20

(0.86,1.66)

0.29 0.96

(0.65,1.41)

0.84 1.09

(0.85,1.40)

0.49 0.40218

CCL22 1.01

(0.89,1.15)

0.85 1.07

(0.91,1.25)

0.42 1.03

(0.94,1.14)

0.51 0.61219

IL13 1.22

(0.86,1.72)

0.27 0.92

(0.59,1.42)

0.69 1.09

(0.83,1.43)

0.53 0.32220

FLT3L 1.18

(0.86,1.61)

0.30 0.96

(0.68,1.35)

0.82 1.08

(0.85,1.35)

0.54 0.39221

CXCL1 1.03

(0.89,1.19)

0.71 1.05

(0.88,1.25)

0.61 1.04

(0.93,1.16)

0.54 0.88222

SERPINA12 0.99

(0.90,1.09)

0.85 1.14

(0.96,1.35)

0.13 1.03

(0.94,1.12)

0.55 0.16223

TFPI 1.25

(0.85,1.84)

0.26 0.96

(0.68,1.35)

0.81 1.08

(0.83,1.39)

0.57 0.31224

CXCL5 1.03

(0.94,1.14)

0.49 1.00

(0.89,1.12)

1.00 1.02

(0.95,1.10)

0.61 0.65225

PAI 1.07

(0.91,1.27)

0.41 0.99

(0.83,1.18)

0.90 1.03

(0.91,1.17)

0.61 0.51226

IL1RL2 0.94

(0.71,1.26)

0.70 1.24

(0.88,1.74)

0.23 1.06

(0.85,1.32)

0.63 0.24227

CA5A 0.99

(0.84,1.16)

0.88 0.95

(0.77,1.16)

0.60 0.97

(0.86,1.10)

0.66 0.76228

CST5 1.19

(0.92,1.54)

0.19 0.85

(0.62,1.18)

0.33 1.04

(0.85,1.28)

0.67 0.11229

IL17RA 1.10

(0.89,1.36)

0.36 0.93

(0.71,1.22)

0.62 1.04

(0.88,1.22)

0.68 0.34230

FGF19 1.14

(0.97,1.35)

0.12 0.89

(0.74,1.08)

0.24 1.03

(0.91,1.16)

0.68 0.055231

IL1RT2 0.99

(0.74,1.32)

0.95 0.92

(0.67,1.26)

0.61 0.96

(0.77,1.19)

0.70 0.74232

MMP10 1.25

(1.00,1.55)

0.046 0.76

(0.57,1.00)

0.052 1.03

(0.87,1.23)

0.72 0.005823

3MCP4 1.0

7(0.85,1.34)

0.57 0.99

(0.79,1.24)

0.94 1.03

(0.88,1.21)

0.73 0.64234

HGDNF 1.05

(0.78,1.43)

0.73 1.02

(0.68,1.54)

0.91 1.04

(0.82,1.33)

0.73 0.91235

TNF 1.05

(0.76,1.44)

0.79 1.03

(0.71,1.51)

0.86 1.04

(0.81,1.33)

0.75 0.97236

CTRC 0.94

(0.78,1.13)

0.50 1.03

(0.85,1.26)

0.76 0.98

(0.86,1.12)

0.78 0.49237

GIF 0.94

(0.83,1.07)

0.34 1.12

(0.97,1.30)

0.13 1.01

(0.92,1.12)

0.78 0.079238

TPA 1.11

(0.88,1.41)

0.37 0.96

(0.78,1.17)

0.68 1.02

(0.88,1.19)

0.79 0.34239

PRSS27 0.88

(0.66,1.17)

0.38 1.30

(0.92,1.85)

0.14 1.03

(0.82,1.28)

0.80 0.089240

LEP 1.01

(0.84,1.21)

0.91 1.03

(0.83,1.28)

0.80 1.02

(0.89,1.17)

0.80 0.90241

MARCO 0.96

(0.66,1.38)

0.81 1.06

(0.83,1.35)

0.66 1.02

(0.84,1.26)

0.81 0.65242

CPA1 1.00

(0.83,1.20)

0.98 1.02

(0.84,1.25)

0.81 1.01

(0.88,1.16)

0.86 0.87243

ADA 1.11

(0.85,1.46)

0.45 0.83

(0.61,1.14)

0.26 0.98

(0.80,1.21)

0.87 0.17244

FGF5 1.15

(0.76,1.75)

0.51 0.88

(0.55,1.43)

0.61 1.03

(0.75,1.41)

0.87 0.42

Protein* Discovery Replication Combined1

OR 95% CI P-value

OR 95% CI P-value

OR 95% CI P-value

P-value224

5CD6 1.0

4(0.82,1.31)

0.76 0.91

(0.69,1.22)

0.54 0.99

(0.82,1.18)

0.88 0.50246

LPL 0.96

(0.68,1.35)

0.82 1.00

(0.75,1.34)

0.97 0.99

(0.79,1.23)

0.90 0.85247

CTSD 1.06

(0.78,1.43)

0.71 0.93

(0.70,1.24)

0.62 0.99

(0.80,1.22)

0.91 0.54248

CD244 1.36

(0.97,1.90)

0.074 0.70

(0.48,1.02)

0.060 1.01

(0.79,1.30)

0.92 0.010249

IL20RA 0.94

(0.57,1.54)

0.79 1.39

(0.54,3.57)

0.50 1.02

(0.66,1.58)

0.93 0.47250

CCL24 1.04

(0.89,1.21)

0.62 0.96

(0.81,1.15)

0.67 1.00

(0.90,1.13)

0.93 0.52251

CDH5 0.97

(0.71,1.32)

0.84 1.02

(0.75,1.38)

0.91 0.99

(0.80,1.23)

0.95 0.82252

SCF 0.73

(0.48,1.09)

0.12 1.25

(0.88,1.77)

0.21 0.99

(0.76,1.29)

0.95 0.047

Legend: Matching variables: age, sex, cohort, follow-up time; Clinical risk factors: smoking, diabetes, history of CAD, antihypertensive treatment, BMI, SBP, heart rate and creatinine).Notes: 1Combined OR and 95% CI from fixed-effect meta-analysis of adjusted ORs from Phase 1a and 1b. 2P-value from test for heterogeneity.*Entry name from UniProt Knowledgebase (UniProtKB).(Note that the proteins are sorted in order of statistical significance of the combined results).

Supplemental Table 3. Bootstrap selection (5,000 models) ranking the 39 top proteins by the % of times selected

Rank Protein* Number (%) of times selected

1 NTPROBNP 5,000 (100.00)2 TWEAK 5,000 (100.00)3 TRAILR2 2,460 (49.20)4 ENRAGE 1,267 (25.34)5 CASP8 1,174 (23.48)6 SLAMF7 911 (18.22)7 TGM2 841 (16.82)8 GDF15 830 (16.60)9 LOX1 720 (14.40)

10 TNFRSF13B 683 (13.66)11 FGF23 595 (11.90)12 CCL16 534 (10.68)13 SLAMF1 298 (5.96)14 SORT1 171 (3.42)15 IL4RA 165 (3.30)16 FABP4 149 (2.98)17 CEACAM8 142 (2.84)18 ACE2 129 (2.58)19 CD4 117 (2.34)20 VEGFD 117 (2.34)21 OPN 78 (1.56)22 MMP12 73 (1.46)23 PLGF 63 (1.26)24 RARRES2 59 (1.18)25 PSPD 57 (1.14)26 PDL2 54 (1.08)27 TNFRSF10A 53 (1.06)28 PAR1 45 (0.90)29 GAL9 35 (0.70)30 TNFRSF11A 30 (0.60)31 IGFBP7 28 (0.56)32 AGRP 25 (0.50)33 IGFBP2 20 (0.40)34 SPON2 19 (0.38)35 IL27 16 (0.32)36 IL16 15 (0.30)37 ADM 13 (0.26)38 KIM1 5 (0.10)

*Entry name from UniProt Knowledgebase (UniProtKB).(Note that the proteins are sorted in order of statistical significance of the combined results).

Supplemental Table 4. Intermediate nodes used in knowledge-based network shown in Figure 4Node* Name UniProt ID*ADAM9 A Disintegrin And Metalloproteinase Domain 9 Q13443

BAFFTumor necrosis factor ligand superfamily member 13B (TNFSF13B) Q9Y275

FAM20C FAM20C, golgi associated secretory pathway kinase Q8IXL6FAS Fas Cell Surface Death Receptor  P25445Ghrelin-28-C10 O-decanoylated Ghrelin-28 (24-51) Ghrelin-28-C10 Q9UBU3

HNF1A hepatocyte nuclear factor 1 homeobox A P22361IGF1 Insulin Like Growth Factor 1 P05019IGF2 Insulin Like Growth Factor 2 P01344Integrin a4b1 Integrin α4β1 (Very Late Antigen-4)  P13612; P05556Integrin a9b1  Integrin α9β1 Q13797; P05557NF-kB** NF-κB complex CORUM Complex ID: 2084NRP2 Neuropilin 2 (Receptor For VEGF165 And Semaphorins Class3) O60462PI4KA Phosphatidylinositol 4-Kinase Alpha P42356TP53 Tumor Protein P53 Tetramer P04637TP73 Tumor Protein P73 Tetramer O15350TRAF2 TNF Receptor Associated Factor 2 Q12933VAMP3 Vesicle Associated Membrane Protein 3 Q15836

*Entry name of proteins from UniProt Knowledgebase (UniProtKB)** except for NF-κB

Supplemental Figure 1. Random forest top proteins

A) Identified top biomarkers and their variable importance; B) Variable importance histogram of all variables.

Supplemental Figure 2. Decision tree for incident heart failure (detailed version)

Legend: BNP was the major discrimination factor to split between heart failure case and control. In the case of low BNP, TWEAK and TRAILR2 may be suitable for confirming HF cases in smaller populations. In the case of high BNP, PON3 and GDF15 offer little classification improvement.Values in criteria are log2-normalized protein expression (NPX) measured by Olink Proseek® Multiplex panels

Supplemental Figure 3. Area under curve of the decision tree presented in Figure 3.