Table 3.

Potential HFpEF candidates based on network proximity to comorbidity profiles. Genes are sorted by functional groups. Rank indicates prediction rank for HFpEF. TF transcription factor, CM cardiomyopathy

Rank	Gene symbol	Gene name	Functional group	Gene function	Role in HF (exemplary or putative)	References
17	PCSK5	Proprotein convertase subtilisin/kexin type 5	Cell differentiation	Mediates post translational endoproteolytic processing	Cleaves GDF1, heart development	[63, 64]
9	NKX2-5	NK2 Homeobox 5	Cell differentiation	TF expressed in precursor cardiac cells, involved in cardiac development	Heart development, activated in HF involved in hypertrophy	[65, 66]
31	GATA5	GATA binding protein 5	Cell differentiation	TF, involved in embryonic development of the heart	Possible role in cardiac hypertrophy, linked to dilated CM	[67]
42	GATA3	GATA binding protein 3	Cell differentiation	TF, involved in embryonic development of the heart and immune cell differentiation	Role in T-cell recruitment	[68, 69]
67	JAG1	Jagged canonical Notch ligand 1	Cell differentiation	Interacts with four receptors in the mammalian Notch signaling pathway	Possible protective role against PAH and diabetic CM, involved in regenerative capacity of the heart	[70–72]
62	NOTCH1	Notch receptor 1	Cell differentiation	Regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands	Possible protective role against PAH and diabetic CM, involved in regenerative capacity of the heart	[70–72]
13	CITED2	Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2	Cell differentiation	TF that controls pluripotency among others	Cardiomyocyte pluripotency	[73]
23	KLKB1	Kallikrein B1	Coagulation	Factor XII activation	Interacts with LDL, possible HF biomarker	[74–76]
27	TBXA2R	Thromboxane A2 receptor	Coagulation	G protein-coupled thromboxane A2 receptor that induces platelet aggregation and regulate hemostasis	Involved in endothelial homeostasis, angiogenesis	[77–79]
34	THBD	Thrombomodulin	Coagulation	Endothelial-specific type I membrane receptor that binds thrombin	Angiogenesis and anticoagulant, possible HF biomarker	[80, 81]
11	DAB2IP	DAB2 interacting protein	Endothelial dysfunction	Ras GTPase-activating protein (GAP)	Associated with endothelial dysfunction in atherosclerosis	[82, 83]
77	ESR1	Estrogen receptor1	Endothelial dysfunction	Estrogen receptor and ligand-activated TF	Regulates NOS activity among many other effects	[84]
7	ATF6	Activating transcription factor 6	ER-stress	Unfolded protein response	Activates XBP1 which modulates ER-stress	[85–87]
3	MMP1	Matrix metallopeptidase 1	Fibrosis	Proteases involved in degrading of ECM	involved in cardiac fibrosis	[88]
25	FGFR2	Fibroblast growth factor receptor 2	Fibrosis	Receptor tyrosine kinases that promote mitogenic signal mediators that induce cell proliferation and survival	Involved in cardiac fibrosis	[89]
33	LOX	Lysyl oxidase	Fibrosis	Cross-linking of collagens	Possible role in myocardial stiffness	[90]
2	MYH7	Myosin heavy chain 7	Hypertrophy	Part of the thick filament in cardiac muscle, involved in contraction	Cardiac hypertrophy marker	[91, 92]
4	SUZ12	SUZ12 polycomb repressive complex 2 subunit	Hypertrophy	Core PRC2 (polycomb repressive complex 2) protein	Mediates long non-coding RNA Ahit induced cardiac hypertrophy	[93]
65	FSTL1	Follistatin like 1	Hypertrophy	Extracellular glycoprotein	Protective against hypertrophy	[94, 95]
79	RGS5	Regulator of G protein signaling 5	Hypertrophy	RGS proteins are involved in the regulation of heterotrimeric G proteins by acting as GTPase activators	Protects from cardiac hypertrophy and fibrosis	[96, 97]
89	CD14	Cluster of differentiation 14	Inflammation	Membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation	Monocytes/macrophages marker in immune disease	[98]
47	SHARPIN	SHANK associated RH domain interactor	Inflammation	Displacing talin from the integrin cytoplasmic domain	Involved in integrin Inactivation and NF-κB Signaling	[99, 100]
90	CD209	Cluster of differentiation 209	Inflammation	Expressed by macrophages and dendritic cells	Involved in rheumatoid arthritis	[101]
36	MVK	Mevalonate kinase	Metabolism	Cholesterol metabolism	Fibrotic effects, Rho family small GTPase activity modulation	[102, 103]
1	DAPK1	Death associated protein kinase 1	Oxidative stress	Calcium/calmodulin-dependent serine/threonine kinase	Protection from oxidative stress in MI	[101]
18	XDH	Xanthine dehydrogenase	Oxidative stress	Oxidative metabolism of purines	Linked to nitroso-redox balance, also possible plasma marker	[104]
69	NOS1	Nitric oxide synthase 1	Oxidative stress	Synthesizing nitric oxide from L-arginine	Inhibition possibly linked to protection of diastolic dysfunction	[105, 106]
14,19	GSTZ1, GSTT1	Glutathione-S-transferases	Oxidative stress	Catalyzing the conjugation of the reduced form of glutathione to xenobiotic substrates for the purpose of detoxification	Related to oxidative stress in cardiac tissue	[107, 108]