Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures : a cohort and Mendelian randomisation investigation

Uppsala universitet, Medicinsk epidemiologi Uppsala universitet, Klinisk epidemiologi Uppsala universitet, Molekylär epidemiologi Uppsala universitet, Klinisk farmakogenomik och osteoporos 2025

Background How cardiovascular diseases (CVD) predispose to a higher risk of fragility fractures is not well understood. Both contribute to significant components of disease burden and health expenditure. Poor bone quality, central obesity, sarcopenia, falls, and low grip strength are independent risk factors for hip and other fragility fractures and also for CVD and early death. Methods We used proteomics and a cohort design combined with Mendelian randomisation analysis to understand shared mechanisms for developing CVD and fragility fractures, two significant sources of disease burden and health expenditure. We primarily aimed to discover and replicate the association of 274 cardio-metabolic-related proteins with future rates of hip and any fracture in two separate population-based cohorts, with a total of 12,314 women and men. Findings The average age at baseline was 68 years in the discovery cohort of women and 74 years in the mixed-sex replication cohort. During 100,619 person-years of follow-up, 2168 had any fracture, and 538 had a hip fracture. Our analysis resulted in 24 cardiometabolic proteins associated with fracture risk: 20 with hip fracture, 9 with any fracture, and 5 with both. The associations remained even if protein concentrations were measured from specimens taken during preclinical stages of cardio-metabolic diseases, and 19 associations remained after adjustment for bone mineral density. Twenty-two of the proteins were associated with total body fat mass or lean body mass. Mendelian randomisation (MR) analysis supported causality since genetically predicted levels of SOST (Sclerostin), CCDC80 (Coiled-coil domain-containing protein 80), NT-proBNP (N-terminal prohormone brain natriuretic peptide), and BNP (Brain natriuretic peptide) were associated with risk of hip fracture. MR analysis also revealed a possible negative impact on bone mineral density (BMD) by genetically predicted higher levels of SOST, CCDC80, and TIMP4 (Metalloproteinase inhibit

Cardiology and Cardiovascular Disease; Kardiologi och kardiovaskulära sjukdomar; Article in journal; info:eu-repo/semantics/article; text

10.1016.j.ebiom.2025.105580

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info:eu-repo/semantics/openAccess

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UPE oai:DiVA.org:uu-549751
0000-0003-2815-1217
0000-0003-2891-9273
0000-0003-3461-1056
0000-0003-2071-5866
0000-0003-2335-8542
0000-0002-0012-1211
0000-0002-0149-452x
0000-0003-2747-1606
0000-0003-0118-0341
0000-0001-5055-5627
0000-0002-6857-5973
0000-0002-4421-6466
doi:10.1016/j.ebiom.2025.105580
PMID 39919333
ISI:001423870700001
Scopus 2-s2.0-85216975680
1511780873

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