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
From: A network medicine approach to study comorbidities in heart failure with preserved ejection fraction
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
27 | TBXA2R | Thromboxane A2 receptor | Coagulation | G protein-coupled thromboxane A2 receptor that induces platelet aggregation and regulate hemostasis | Involved in endothelial homeostasis, angiogenesis | |
34 | THBD | Thrombomodulin | Coagulation | Endothelial-specific type I membrane receptor that binds thrombin | Angiogenesis and anticoagulant, possible HF biomarker | |
11 | DAB2IP | DAB2 interacting protein | Endothelial dysfunction | Ras GTPase-activating protein (GAP) | Associated with endothelial dysfunction in atherosclerosis | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 |