Table 2 |.
Biological plausibility of key proteins in relation to the target physiology for each model; the top three mathematical contributors to each model’s output are shown
| issue | Model | Top three proteins | Potential role in target biology |
|---|---|---|---|
| Current health state | Liver fat: presence/absence (ultrasound) | SEZ6L (seizure 6-like protein) | Genetic marker for cardiometabolic conditions and associated with an unhealthy lifestyle score (BMI status, physical activity, smoking and alcohol habits) |
| FABPA (fatty acid-binding protein, adipocyte) | Expressed in adipocytes; strongly linked to metabolic and inflammatory pathways; increased hepatic expression and circulating levels of A-FABP (FABP-4) have been observed in patients with nonalcoholic fatty liver disease | ||
| IGFBP-1 (insulin-like growth factor-binding protein 1) | Synthesized in the liver and plays a role in metabolism regulation and insulin resistance | ||
| Kidney function: eGFR <60 ml min−1 | TMEDA (transmembrane emp24 domain-containing protein 10) | Involved in kidney development | |
| Apo A-IV (apolipoprotein A-IV) | Lipid-binding protein but also a known association with kidney disease | ||
| Beta-2 microglobulin | Well-known clinical measure of kidney filtration | ||
| Body fat: % | Leptin | Produced in adipose tissue, and present in higher amounts in subjects with high BMI and percentage body fat; previously shown to enhance the accuracy of BMI estimates of percentage body fat when DEXA was unavailable | |
| FABP (fatty acid-binding protein) | Involved in active fatty acid metabolism and correlated with fatty liver, diabetic nephropathy and metabolic syndrome | ||
| SFRP4 (secreted frizzled-related protein 4) | Elevated in obesity and involved in obese adipose tissue pathophysiology | ||
| Lean body mass: kg | SEZ6L | Genetic marker for cardiometabolic conditions and associated with an unhealthy lifestyle score (BMI status, physical activity, smoking and alcohol habits) | |
| SLIK4 SLIT and NTRK protein-like 4 | Involved in synaptogenesis and neurite growth; no clear connection to target biology. | ||
| WISP-2 | Secreted adipokine increased in obesity and insulin resistance in subcutaneous adipose tissue | ||
| Visceral fat: kg | Leptin | Produced in adipose tissue and present in higher amounts in subjects with high BMI and percentage body fat; has also been shown to enhance the accuracy of BMI estimates of percentage body fat when DEXA unavailable | |
| FABPA | Strongly linked to metabolic and inflammatory pathways; found in adipocytes | ||
| INHBC | Inhibins have been shown to play a role in body composition and energy expenditure | ||
| Cardiopulmonary fitness V02 max: ml kg−1 min−1 | Leptin | Produced in adipose tissue and present in higher amounts in subjects with high BMI and percentage body fat; has also been shown to enhance the accuracy of BMI estimates of percentage body fat when DEXA unavailable | |
| C1QR1 (complement component C1Q receptor) | Part of the innate immune system | ||
| GGH (gamma glutaryl hydrolase) | Regulates intracellular folate; energy production and rebuilding and repair of muscle tissue by physical activity require folate | ||
| Modifiable behavioral factors | Alcohol consumption: above/below 14 units (women) | SCUB1 (signal peptide, CUB and EGF-like domain-containing protein 1) | Promotes platelet-platelet interaction and is a biomarker of platelet activation in acute thrombotic diseases; may relate to impact of alcohol on platelets |
| SERC (phosphoserine aminotransferase) | No known/clear relation with target physiology | ||
| SCF (stem cell factor) kit ligand | Mainly involved in hematopoiesis in adults; may relate to alcohol effects on hematopoiesis | ||
| Alcohol consumption: above/below 14 units (men) | SCUB1 | Promotes platelet-platelet interaction and is a biomarker of platelet activation in acute thrombotic events; may relate to impact of alcohol on platelets | |
| PTPRJ (receptor-type tyrosine-protein phosphatase eta) | Modulator of cell signaling; no known/clear relation with target physiology | ||
| Apo F (apolipoprotein F) | Important role in lipid metabolism; biomarker for cirrhosis in patients with hepatitis C; associated with advancing fibrosis in fatty liver disease; may relate to alcohol effect on liver | ||
| Weekly physical activity: kcal d−1 | Leptin | Produced in adipose tissue and present in higher amounts in subjects with high BMI and percentage body fat | |
| IGLO5 (IgLON family member 5) | Immunoglobulin adhesion molecule; no known/clear relation with target physiology | ||
| ATF6A (cyclic AMP-dependent transcription factor ATF-6 alpha) | Transcription activator that initiates the unfolded protein response during endoplasmic reticulum stress | ||
| Cigarette smoking: current yes/no | SLIK3 (SLIK and NTR protein-like 3) | Involved in neurite growth; no known/clear relation with target physiology | |
| Secretoglobin family 3 A member 1 | Associated with chronic obstructive airways disease and prognosis in non-small-cell lung cancer | ||
| TM108 (transmembrane protein 108) | Genome-wide Association Study linked this with successful smoking cessation | ||
| Future metabolic health risks | Conversion from pre-diabetes to diabetes within 10 years, above or below 3× risk | LPH (lactase-phlorizin hydrolase) | No known/clear relation with target physiology |
| Quinone reductase 2 | Flavoprotein that catalyzes metabolic reduction of quinones; quinone reductase may play a role in insulin secretion | ||
| Prolylcarboxypeptidase | Key enzyme that degrades α-melanocyte-stimulating hormone to an inactive form unable to inhibit food intake; viewed as a therapeutic target for the treatment of metabolic disorders such as obesity and diabetes | ||
| Relative probability of a first CV event within 5 years (1–6×) | Gelsolin | Regulates dynamic actin filament organization, cell morphology, differentiation, movement and apoptosis; overexpression has been shown to induce cardiac hypertrophy | |
| Antithrombin III | Inactivates several enzymes of the coagulation system; may play a role in the progression of atherosclerosis and in the pathogenesis of acute coronary syndromes | ||
| sTREM-1 | Amplifies neutrophil- and monocyte-mediated inflammatory responses; levels rise significantly in all types of CVD and associated organ dysfunction |
A full listing of all 891 proteins in all models is shown in Supplementary Table 1, and all proteins that were measured are listed in Supplementary Table 3.