Table 3.

Associations of protein levels with incident heart failure in multivariable-adjusted models

	Meta-Analysis		Discovery (FHS)			Replication (HUNT)
Protein	HR (95% CI)	P-value	HR (95% CI)	P-value	FDR	HR (95% CI)	P-value	Heterogeneity I²
NT-proBNP^*	1.78 (1.52-2.08)	3.5E-13	1.37 (1.06-1.76)	0.02	0.35	2.08 (1.71-2.53)	2.6E-12	0.85
ErbB1	0.68 (0.59-0.78)	4.4E-08	0.67 (0.55-0.82)	0.00006	0.04	0.69 (0.57-0.84)	0.00017	0.00
MBL	1.29 (1.15-1.45)	1.2E-05	1.32 (1.13-1.55)	0.0006	0.08	1.26 (1.07-1.48)	0.0055	0.00
RGMC	0.77 (0.69-0.87)	2.0E-05	0.74 (0.63-0.88)	0.0008	0.08	0.80 (0.68-0.94)	0.007	0.00
GDF-11/8	0.77 (0.68-0.87)	3.0E-05	0.74 (0.63-0.88)	0.0006	0.08	0.80 (0.67-0.96)	0.014	0.00
TSP2	1.29 (1.14-1.45)	3.1E-05	1.35 (1.14-1.59)	0.0006	0.08	1.23 (1.05-1.45)	0.013	0.00
NRP1^*	1.34 (1.16-1.54)	6.8E-05	1.34 (1.06-1.70)	0.01	0.35	1.33 (1.11-1.59)	0.0016	0.00
vWF	1.29 (1.14-1.46)	7.6E-05	1.44 (1.20-1.73)	0.00007	0.04	1.16 (0.98-1.38)	0.093	0.66
Apo E4	0.78 (0.69-0.88)	8.9E-05	0.74 (0.62-0.89)	0.001	0.09	0.82 (0.69-0.97)	0.022	0.00
Apo E3	0.79 (0.70-0.90)	0.0002	0.75 (0.63-0.89)	0.001	0.09	0.84 (0.70-1.00)	0.056	0.00
RGMA^*	0.77 (0.67-0.89)	0.0003	0.69 (0.53-0.90)	0.006	0.25	0.80 (0.68-0.95)	0.011	0.00
Notch 1	0.79 (0.70-0.90)	0.0003	0.74 (0.62-0.88)	0.0007	0.08	0.86 (0.72-1.03)	0.094	0.26
Mn SOD	0.80 (0.71-0.91)	0.0004	0.74 (0.63-0.87)	0.0004	0.08	0.88 (0.73-1.05)	0.17	0.47
RGMB	0.81 (0.72-0.91)	0.0004	0.76 (0.64-0.89)	0.001	0.09	0.86 (0.73-1.02)	0.082	0.12
IL-1Ra^*	1.29 (1.12-1.49)	0.0005	1.34 (1.00-1.80)	0.05	0.5	1.27 (1.08-1.50)	0.004	0.00
NEGR1^*	0.78 (0.67-0.90)	0.0007	0.65 (0.50-0.84)	0.0009	0.09	0.85 (0.71-1.01)	0.064	0.65
Apo L1^*	0.79 (0.69-0.91)	0.001	0.67 (0.52-0.87)	0.002	0.14	0.85 (0.72-1.01)	0.063	0.56
ISLR2^*	0.80 (0.69-0.92)	0.002	0.74 (0.58-0.93)	0.01	0.32	0.84 (0.70-1.00)	0.047	0.00
VEGF sR2	0.82 (0.72-0.93)	0.003	0.75 (0.63-0.89)	0.001	0.09	0.92 (0.76-1.11)	0.39	0.60
S100A12^*	1.23 (1.07-1.41)	0.003	1.35 (1.05-1.73)	0.02	0.37	1.18 (1.00-1.40)	0.043	0.00
NCAM-120	0.84 (0.74-0.95)	0.007	0.73 (0.61-0.87)	0.0006	0.08	0.97 (0.81-1.17)	0.75	0.79
TNF alpha^*	1.15 (1.01-1.32)	0.04	1.35 (1.04-1.76)	0.02	0.4	1.09 (0.93-1.28)	0.31	0.49
MIC-1^*	1.18 (1.01-1.39)	0.04	1.43 (1.03-1.98)	0.03	0.44	1.12 (0.93-1.34)	0.25	0.40
DKK4	0.89 (0.79-0.99)	0.04	0.74 (0.62-0.88)	0.0007	0.08	1.01 (0.88-1.17)	0.86	0.86
Cathepsin D^*	1.15 (1.00-1.33)	0.06	1.39 (1.06-1.81)	0.02	0.35	1.07 (0.90-1.26)	0.47	0.63
IgG^*	0.88 (0.77-1.02)	0.08	0.75 (0.59-0.96)	0.02	0.37	0.96 (0.81-1.14)	0.64	0.61
PEX5^*	0.91 (0.79-1.04)	0.15	0.75 (0.60-0.95)	0.02	0.37	0.99 (0.84-1.16)	0.91	0.72
C7	1.08 (0.96-1.22)	0.21	1.41 (1.19-1.68)	0.0001	0.04	0.85 (0.72-1.00)	0.048	0.94
BMPR1A^†	--	--	0.74 (0.63-0.88)	0.0006	0.08	--	--	--

Abbreviations: NT-proBNP, N-terminal proB-type natriuretic peptide; ErbB1, epidermal growth factor receptor; MBL, mannose binding lectin; RGMC, repulsive guidance molecule C (hemojuvelin); GDF-11/8, growth/differential factor 11/8; TSP2, thrombospondin-2; NRP1, neuropilin 1; vWF, von Willebrand factor; Apo E4, apolipoprotein E (isoform E4); Apo E3, apolipoprotein E (isoform E3); RGMA, repulsive guidance molecule A; Mn SOD, superoxide dismutase [Mn], mitochondrial; Notch 1, neurogenic locus notch homolog protein 1; RGMB, RGM domain family member B; IL-1Ra, interleukin 1 receptor antagonist; NEGR1, neuronal growth regulator 1; Apo L1, apolipoprotein L1; ISLR2, immunoglobulin superfamily containing leucine rich repeat 2; VEGF sR2, vascular endothelial growth factor receptor 2; S100A12, S100 calcium binding protein A12; NCAM-120, neural cell adhesion molecule 1, 120 kDa isoform; TNF-a, tumor necrosis factor alpha; MIC-1, macrophage inhibitor cytokine 1; DKK4, Dickkopf-related protein 4; IgG, immunoglobulin G; PEX5, peroxisomal biogenesis factor 5; C7, complement component 7; BMPR1A, bone morphogenetic protein receptor type 1A

Hazard ratios represent the relative hazard for a 1 SD increment in the transformed and normalized protein level

Multivariable model was adjusted for age, sex, body mass index, hypertension treatment, systolic blood pressure, total/HDL cholesterol, diabetes, smoking, prior myocardial infarction, and interim myocardial infarction

False discovery rate (FDR) value <0.10 was used to determine statistical significance in the discovery sample

Protein was measured on second “run” of SomaLogic platform (1.3k) only in FHS. Proteins not marked with an asterisk were measured in the full sample.

^†

BMPR1A was not measured in HUNT