Proteomics, CVD, and bone phenotypes




Principal Investigator:

Karl Michaëlsson


Uppsala universitet

Start Date:


End Date:


Primary Classification:

30211: Orthopaedics



Cardiovascular diseases, stroke, peripheral and aortic calcifications predispose to future higher risk of both hip fracture and other types of frailty fractures, independent of previously recognized clinical risk factors. Conversely, increased bone resorption, osteoporosis, and prior frailty fractures are associated with higher rates of cardiovascular events in both women and men. Identical co-twin control analyses indicate that common genes may predispose to the development of both CVD and fractures.1 Interestingly, the age-adjusted incidence of both myocardial infarction and stroke declined in Sweden by more than 40% during 1998-2016, and hip fracture rates also declined in parallel. The lower fracture rates are not explained by bisphosphonate use, at an ecological level. Since there exists strong indications of common disease pathways for the occurrence of frailty fractures and CVD, we need to better understand these mechanisms; from genes and lifestyle to disease occurrence. Proteomics offer new possibilities for investigating the molecular underpinnings of these chronic diseases. While rigorously conducted genomic discovery and replication studies have been accomplished,16 similar proteomic replication analyses are hitherto non-existent. Only one recent cohort project, of 1800 men, has used proteomics and linkage to BMD. Twenty annotated proteins were identified as related to BMD and five of these were further associated to incident hip fractures. No replication cohort was used, fracture related proteins independent of BMD were not identified, the concentration of proteins was estimated from peptide compositions and not directly measured, and the most abundant serum proteins were deleted from the samples. Comprehensive studies, including simultaneous information about ‘omics’ with a discovery and replication design are therefore needed. Such information, together with longitudinal lifestyle data, can discover common pathogenic pathways between CVD and fractures, including via BMD, fat mass or sarcopenia. Causal inference of identified risk proteins can be accomplished by a complementary Mendelian randomized design.18 We therefore aimed to identify novel protein biomarkers of risk for frailty fractures ̶ shared or non-shared with BMD, fat or lean muscle mass ̶ using proteomics, genomics and lifestyle information, also aiming to discover common pathogenic mechanisms for cardiovascular diseases and fractures.