Marioni, Riccardo

Evans, Kathy

Price, Jackie

Chybowska, Aleksandra Daria

Medical Research Council (MRC)

Medical Research Council Doctoral Training Program

University of Edinburgh: College of Medicine and Veterinary Medicine

2026-05-13T15:45:37Z

2026-05-13

BACKGROUND: The serum proteome can provide valuable insights into the development and progression of diseases. This is particularly important for cardiovascular disease (CVD), a leading cause of death worldwide. In this large-scale cohort study, we employ an untargeted massspectrometry- based approach to explore associations between highly expressed proteins, incident CVD (analysed as six individual outcomes and one composite outcome) and all-cause mortality. METHODS: The abundances of 439 proteins and protein groups quantified by mass spectrometry in serum were related to incident outcomes in 8,343 Generation Scotland participants (age 40–69 years), who were free of CVD at baseline (nall_cause_death=618, ncomposite_CVD=666, follow-up ≤17 years). Cox proportional hazards (PH) models were run before and after adjustment for preselected known CVD risk factors. Sex-specific effects were explored. A protein-based risk score for composite CVD outcome was developed using penalised regression. RESULTS: Forty-eight high abundance serum proteins and protein groups were significantly associated with incident CVD and death outcomes (PBonferroni<1.14x10-4), including 24 associations not reported in the Open Targets database. Proteins involved in immune and oxidative stress responses were associated with composite CVD (Immunoglobulin heavy variable 3/OR16-9, Hazard Ratio per SD (HR)=0.85 [95%CI 0.79,0.92]) and death (Alpha-1-antitrypsin, HR=1.27 [1.17, 1.38]), while heart failure was linked to proteins playing a role in lipid metabolism (Apolipoprotein A-II, HR=0.70 [0.59, 0.84]) and complement cascade (Complement C1q subcomponent subunit B, HR=1.40 [1.18, 1.66]). Applied to the test set, the proteomic risk score improved 17-year incident CVD prediction over models including age, sex, and nine lifestyle and clinical risk factors (ΔAUC = 0.010, ROC P = 0.013). CONCLUSION: The highly abundant serum proteome, readily assessed by mass spectrometry, reveals candidate biomarkers for incident CVD and provides predictive value for early risk stratification.

https://era.ed.ac.uk/handle/1842/44693

https://doi.org/10.7488/era/7208

en

A blood- and brain-based EWAS of smoking Chybowska, A. D., Bernabeu, E., Yousefi, P., Suderman, M., Hillary, R. F., Clark, R., MacGillivray, L., Murphy, L., Harris, S. E., Corley, J., Campbell, A., Spires-Jones, T. L., McCartney, D. L., Cox, S. R., Price, J. F., Evans, K. L. & Marioni, R. E., 4 Apr 2025, In: Nature Communications. 16, 1, 3210

Blood- and brain-based genome-wide association studies of smoking Chybowska, A. D., Bernabeu, E., Yousefi, P., Suderman, M., Hillary, R. F., Macgillivray, L., Murphy, L., Harris, S. E., Corley, J., Campbell, A., Spires-Jones, T. L., McCartney, D. L., Cox, S. R., Price, J. F., Evans, K. L. & Marioni, R. E., 21 May 2024, medRxiv

Epigenetic Contributions to Clinical Risk Prediction of Cardiovascular Disease Chybowska, A. D., Gadd, D. A., Cheng, Y., Bernabeu, E., Campbell, A., Walker, R. M., McIntosh, A. M., Wrobel, N., Murphy, L., Welsh, P., Sattar, N., Price, J. F., McCartney, D. L., Evans, K. L. & Marioni, R. E., 30 Jan 2024, (E-pub ahead of print) In: Circulation: Genomic and Precision Medicine. p. e004265

Cardiovascular Disease (CVD)

CVD

proteome

Mass Spectrometry

risk prediction models

Predictive Models

Augmenting clinical risk prediction of cardiovascular disease through multi-omics

Thesis

Doctoral

PhD Doctor of Philosophy