Researchers at the University of Iceland and the Icelandic Heart Association have demonstrated the importance of considering the long-term temporal stability of circulating proteins and other biomarkers in disease research. This study is the first of its kind, and the findings are published in the prestigious journal Nature Communications.
Blood Proteins Offer Valuable Insights into Disease
Blood proteins can provide important information about health and disease. Previous studies have shown that levels of specific proteins can help identify biological changes occurring before disease onset, as well as processes activated during illness. Such information holds considerable promise for improving disease risk assessment and advancing personalised healthcare.
Most studies to date, however, have relied on measurements taken at a single point in time. As a result, little is known about how well these measurements reflect an individual's long-term biological profile. Understanding how protein levels change over time, and what factors influence those changes, is thus essential for the development of reliable biomarkers.
To address this question, researchers examined the long-term temporal stability of blood proteins in nearly 3,100 participants from the AGES-Reykjavik Study, with an average age of 75 years. The study included measurements of more than 7,000 proteins collected at two time points approximately five years apart.
The researchers assessed temporal stability by examining how consistent protein levels remained within the same individuals over time. The results showed that while some proteins remained highly stable, others varied considerably. Proteins that are actively secreted into the bloodstream, as well as those specific to particular tissues, were generally among the most stable. In contrast, proteins that showed greater variability over time were more likely to be involved in essential biological processes within cells. This suggests that such proteins may enter the bloodstream primarily through cellular damage or other transient biological events rather than through regulated secretion. Overall, protein levels tended to become more stable with increasing age, and in some cases, differences were observed between men and women. The findings were independently replicated in participants of the U.S.-based Cardiovascular Health Study through collaboration with researchers at the University of Washington and Stanford University.
Genetic Factors and Disease Influence Protein Stability
The study found that genetic factors and disease status had the greatest impact on the long-term temporal stability of protein levels. When protein concentrations were adjusted for genetic effects, many proteins became more variable over time, and some that initially appeared stable were reclassified as variable. These results highlight the important role of genetic factors in determining the long-term temporal stability of circulating protein levels. Disease status also affected protein stability, although the effects differed between diseases. For example, some proteins became more variable following a diagnosis of myocardial infarction, while others became more stable in individuals diagnosed with atrial fibrillation.
According to the researchers, these results highlight the importance of considering temporal stability when investigating proteins and other biomarkers associated with disease. The findings suggest that proteins enter the bloodstream via distinct biological mechanisms, such as active secretion from tissues or leakage due to cellular damage, which may contribute to their varying levels of stability. The study also demonstrates that proteins respond differently to disease processes. A sudden change in a normally stable protein may signal the development or progression of disease, while unusually stable levels of a typically variable protein may also indicate an underlying abnormality. Such insights are particularly important for the development of biomarkers designed to monitor disease progression over time.
The paper's first author is Hulda Karen Ingvarsdóttir, a PhD candidate in Biomedical and Health Sciences at the Faculty of Medicine, University of Iceland. The study builds on her master's research in Bioinformatics, which she has further developed in her doctoral work. The study was led by Valborg Guðmundsdóttir, Research Associate Professor at the University of Iceland’s Faculty of Medicine, and the Icelandic Heart Association. The Helga Jónsdóttir and Sigurliði Kristjánsson Memorial Fund provided funding. The research group's work in proteomics is also supported by the Novo Nordisk Foundation, the U.S. National Institute on Aging, and the Icelandic Research Fund (Rannís). Collaborators from the National Institute on Aging and Novartis also contributed to the study.
The article, "Long-term temporal stability of circulating proteins in older adults," is available in Nature Communications: