Table 2.
Positive controls and repurposing opportunities: prioritised proteins related to plaque vulnerability.
| Protein | Gene name | Uniprot ID | Druggability | Metabolism class(es) | No. breakdown products | Breakdown product–CHD effect | Protein-CHD effect | No. drugs | Cardiac indication and/or side-effect | Cardiac indication(s) | Cardiac side–effect(s) | Drug name(s) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| A2MG | A2M | P01023 | Druggable | Unclassified, Amino Acid | 2 | Increasing | 0.89 (0.85; 0.94) | 1 | No | – | – | Technetium tc 99m succimer |
| ARK72 | AKR7A2 | O43488 | Not yet druggable | Unclassified | 1 | Decreasing | 1.11 (1.08; 1.15) | 0 | No | – | – | |
| APOF | APOF | Q13790 | Not yet druggable | Energy | 1 | Increasing | 1.12 (1.07; 1.17) | 0 | No | – | – | |
| ATF6B | ATF6B | Q99941 | Not yet druggable | Amino Acid | 3 | Mixed | 1.10 (1.08; 1.13) | 0 | No | – | – | |
| AT1B2 | ATP1B2 | P14415 | Drugged | Lipid | 1 | Increasing | 0.97 (0.96; 0.99) | 6 | Yes | See Appendix Table S11 | Arrhythmias, Cardiac conduction disorder | Deslanoside, Digitoxin, Digoxin, Acetyldigitoxin, Istaroxime, Lanatoside c |
| C1S | C1S | P09871 | Drugged | Unclassified | 1 | Decreasing | 1.09 (1.07; 1.11) | 2 | No | – | – | Human c1-esterase inhibitor, Sutimlimab |
| CAH1 | CA1 | P00915 | Drugged | Unclassified, Amino Acid | 3 | Mixed | 1.31 (1.17; 1.48) | 8 | Yes | Pulmonary hypertension, Heart failure | Arrhythmias, Blood pressure disorders | Methocarbamol, Acetazolamide sodium, Dichlorphenamide, Acetazolamide, Methazolamide, Polmacoxib, Ethoxzolamide, Sulthiame |
| COMT | COMT | P21964 | Drugged | Xenobiotics, Unclassified | 2 | Decreasing | 0.75 (0.69; 0.81) | 4 | Yes | – | Myocardial infarction, Chest pain | Tolcapone, Entacapone, Opicapone, Nebicapone |
| CATD | CTSD | P07339 | Not yet druggable | Amino Acid | 1 | Increasing | 0.96 (0.94; 0.97) | 0 | No | – | – | |
| CATH | CTSH | P09668 | Not yet druggable | Xenobiotics | 1 | Decreasing | 0.96 (0.95; 0.97) | 0 | No | – | – | |
| FER | FER | P16591 | Not yet druggable | Unclassified | 1 | Increasing | 0.77 (0.72; 0.82) | 0 | No | – | – | |
| IL6RA | IL6R | P08887 | Drugged | Amino Acid | 1 | Increasing | 0.97 (0.97; 0.98) | 5 | Yes | Non-st elevated myocardial infarction, Pulmonary hypertension | Blood pressure disorders | Tocilizumab, Sarilumab, Vobarilizumab, Levilimab, Satralizumab |
| NAGK | NAGK | Q9UJ70 | Not yet druggable | Unclassified | 1 | Increasing | 1.06 (1.04; 1.09) | 0 | No | – | – | |
| PLTP | PLTP | P55058 | Not yet druggable | Unclassified, Xenobiotics | 2 | Mixed | 1.03 (1.01; 1.04) | 0 | No | – | – | |
| SIG14 | SIGLEC14 | Q08ET2 | Not yet druggable | Unclassified, Amino Acid | 2 | Mixed | 0.99 (0.98; 0.99) | 0 | No | – | – | |
| SWP70 | SWAP70 | Q9UH65 | Not yet druggable | Amino Acid, Lipid | 2 | Mixed | 0.94 (0.93; 0.96) | 0 | No | – | – |
N.B. Each row presents a plasma protein associated with coronary heart disease (CHD), and at least one urinary metabolism breakdown product, where the associations between protein, breakdown product(s), and CHD are directionally concordant (Fig. 2). Associations were identified by Mendelian randomisation.
Protein names are based on their Uniprot synonym. Druggability indicates whether the proteins are targeted by a developmental compound in clinical trials (druggable) or by a compound which has received marketing approval (drugged), based on ChEMBL and the British National Formulary. The metabolism classes represent the identified metabolism origin of the urinary breakdown product. The breakdown product–CHD effect indicates whether the breakdown product's effect on CHD is risk-increasing or risk-decreasing, based on cis-Mendelian randomisation. The protein–CHD effect estimates were obtained from cis-Mendelian randomisation and are presented as odds ratios representing the effect of a one standard deviation increase in protein values, along with corresponding confidence intervals. The No. drug column records the number of approved drugs with affinity for the protein as available in ChEMBL. For more details on metabolism breakdown products and full numerical Mendelian randomisation results please refer to Appendix Table S3. For a full list of the compounds and their indication and side-effects please refer to Appendix Table S11.