Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in context
Summary: 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 inde...
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Elsevier
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425000246 |
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| author | Karl Michaëlsson Rui Zheng John A. Baron Tove Fall Alicja Wolk Lars Lind Jonas Höijer Carl Brunius Eva Warensjö Lemming Olga E. Titova Bodil Svennblad Susanna C. Larsson Shuai Yuan Håkan Melhus Liisa Byberg Hannah L. Brooke |
| author_facet | Karl Michaëlsson Rui Zheng John A. Baron Tove Fall Alicja Wolk Lars Lind Jonas Höijer Carl Brunius Eva Warensjö Lemming Olga E. Titova Bodil Svennblad Susanna C. Larsson Shuai Yuan Håkan Melhus Liisa Byberg Hannah L. Brooke |
| author_sort | Karl Michaëlsson |
| collection | DOAJ |
| description | Summary: 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 inhibitor 4). The MR association with BMD was positive for PTX3 (Pentraxin-related protein) and SPP1 (Osteopontin). Genetically predicted higher concentrations of SOST and lower concentrations of SPP1 also conferred a higher risk of falls and lowered grip strength. The genetically determined concentration of nine proteins influenced fat mass, and one influenced lean body mass. Interpretation: These data reveal biological links between cardiovascular diseases and fragility fractures. The proteins should be further evaluated as shared targets for developing pharmacological interventions to prevent fractures and cardiovascular disease. Funding: The study was supported by funding from the Swedish Research Council (https://www.vr.se; grants No. 2015-03257, 2017-00644, 2017-06100, and 2019-01291 to Karl Michaëlsson) and funding from Olle Engkvist Byggmästares stiftelse (SOEB). |
| format | Article |
| id | doaj-art-eb333e4c94e14859a955208a3cc2d741 |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-eb333e4c94e14859a955208a3cc2d7412025-02-07T04:47:47ZengElsevierEBioMedicine2352-39642025-03-01113105580Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in contextKarl Michaëlsson0Rui Zheng1John A. Baron2Tove Fall3Alicja Wolk4Lars Lind5Jonas Höijer6Carl Brunius7Eva Warensjö Lemming8Olga E. Titova9Bodil Svennblad10Susanna C. Larsson11Shuai Yuan12Håkan Melhus13Liisa Byberg14Hannah L. Brooke15Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenClinical Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USAMolecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, SwedenUnit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenClinical Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenFood and Nutrition Science, Department of Life Sciences, Chalmers University of Technology, Gothenburg, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenUnit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenClinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenMedical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Corresponding author.Summary: 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 inhibitor 4). The MR association with BMD was positive for PTX3 (Pentraxin-related protein) and SPP1 (Osteopontin). Genetically predicted higher concentrations of SOST and lower concentrations of SPP1 also conferred a higher risk of falls and lowered grip strength. The genetically determined concentration of nine proteins influenced fat mass, and one influenced lean body mass. Interpretation: These data reveal biological links between cardiovascular diseases and fragility fractures. The proteins should be further evaluated as shared targets for developing pharmacological interventions to prevent fractures and cardiovascular disease. Funding: The study was supported by funding from the Swedish Research Council (https://www.vr.se; grants No. 2015-03257, 2017-00644, 2017-06100, and 2019-01291 to Karl Michaëlsson) and funding from Olle Engkvist Byggmästares stiftelse (SOEB).http://www.sciencedirect.com/science/article/pii/S2352396425000246Cardiovascular diseasesFragility fracturesCohort studiesMendelian randomisationProteomics |
| spellingShingle | Karl Michaëlsson Rui Zheng John A. Baron Tove Fall Alicja Wolk Lars Lind Jonas Höijer Carl Brunius Eva Warensjö Lemming Olga E. Titova Bodil Svennblad Susanna C. Larsson Shuai Yuan Håkan Melhus Liisa Byberg Hannah L. Brooke Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in context EBioMedicine Cardiovascular diseases Fragility fractures Cohort studies Mendelian randomisation Proteomics |
| title | Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in context |
| title_full | Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in context |
| title_fullStr | Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in context |
| title_full_unstemmed | Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in context |
| title_short | Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigationResearch in context |
| title_sort | cardio metabolic related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures a cohort and mendelian randomisation investigationresearch in context |
| topic | Cardiovascular diseases Fragility fractures Cohort studies Mendelian randomisation Proteomics |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425000246 |
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