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Stein, M. ; Viallon, V.* ; Leitzmann, M.F.* ; Gunter, M.J.* ; Smith-Byrne, K.* ; Ler, P.* ; Ricceri, F.* ; Masala, G.* ; Beigrezaei, S.* ; Koop, Y.* ; Zamora-Ros, R.* ; Jiménez-Zabala, A.* ; Lill, C.M.* ; Riboli, E.* ; Ferrari, P.* ; Freisling, H.*

Proteomics of multimorbidity progression across cardiometabolic diseases and cancer in a multinational cohort.

Cardiovasc. Diabetol. 25:185 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background: Multimorbidity, defined here as the co-occurrence of cardiovascular disease (CVD), type 2 diabetes (T2D), and/or cancer is a major public health challenge. However, its underlying biological mechanisms remain unclear, limiting progress toward identifying shared interventional targets. Methods: We applied large-scale plasma proteomics (SomaScan 7k; 7,289 aptamers) in 13,270 European Prospective Investigation into Cancer and Nutrition (EPIC) participants to identify protein signatures of multimorbidity. We modelled multimorbidity progression as sequential disease transitions, i.e., from the disease-free state at baseline to a first disease and from the first disease to a second disease. Using weighted multivariable Cox regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for risk of cancer, CVD, and T2D. Risk associations were replicated using Olink proteomics in UK Biobank (N = 44,567). Results: We identified 422 aptamers associated with more than one disease (FDR-corrected P < 0.05), e.g., 265 aptamers were shared between CVD and T2D. Thirty-eight aptamers were associated with multimorbidity progression. Among these, 27 aptamers showed consistent positive associations across sequential disease transitions, including SEMA6A (disease-free to cancer HR: 1.14; 95% CI 1.05, 1.23; cancer to T2D HR: 2.61; 95% CI 1.76, 3.80). Four aptamers showed consistent inverse associations, including NLGN1 (disease-free to T2D HR: 0.72; 95% CI 0.61, 0.84; T2D to cancer HR: 0.57; 95% CI 0.43, 0.75). Nineteen of the identified proteins were also measured in UK Biobank, with broadly consistent associations. Conclusions: This study identifies candidate proteins that may indicate molecular pathways to multimorbidity of cardiometabolic diseases and cancer. Future studies should evaluate the causal roles of these proteins for targeted interventions and risk stratification.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Disease ; Cancer ; Biobank ; Cohort ; Cohort Study ; Hazard Ratio ; Multimorbidity ; Prospective Cohort Study
ISSN (print) / ISBN 1475-2840
e-ISSN 1475-2840
Zeitschrift Cardiovascular Diabetology
Quellenangaben Band: 25, Heft: 1, Seiten: , Artikelnummer: 185 Supplement: ,
Verlag Springer
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)