A groundbreaking study from Karolinska Institutet has unveiled a distinctive plasma protein profile that may signal an increased hereditary risk for early-onset coronary heart disease (CHD). This research, recently published in the prestigious journal Circulation: Genomic and Precision Medicine, explores the molecular footprint left by genetic predispositions to atherosclerosis—the primary pathological process underlying many cardiovascular conditions. By scrutinizing the blood plasma of thousands of individuals, the study elucidates a complex interplay between inherited factors and biological markers that foreshadow the development of coronary artery disease.
Delving into the blood samples of over 4,000 participants devoid of clinically diagnosed heart disease, the researchers meticulously correlated protein abundance with documented family histories of cardiovascular events among parents or siblings. The resultant data set revealed 38 distinct proteins elevated in those with familial risk. These proteins predominantly relate to inflammatory pathways and lipid metabolism—two critical domains in the pathogenesis of coronary atherosclerosis. This discovery underscores a previously underappreciated biochemical signature that transcends standard clinical risk factors.
Among the proteins of interest, follistatin and cathepsin D emerged as significantly upregulated in individuals with a hereditary predisposition to coronary artery disease, irrespective of traditional risk determinants such as blood pressure, cholesterol levels, or lifestyle factors. Follistatin, known for its role in opposing transforming growth factor-beta signaling, and cathepsin D, a lysosomal enzyme implicated in extracellular matrix remodeling and apoptosis, may serve as pivotal biomarkers linking genetic inheritance to pathological vascular remodeling.
The study leveraged data from the Swedish CArdioPulmonary bioImage Study (SCAPIS), an extensive population cohort featuring comprehensive health assessments including advanced coronary computed tomography (CT) angiography. The rich integration with national health registers, notably the Swedish Multigenerational Register, enabled the team to definitively associate familial history with coronary atherosclerosis severity, quantitatively expressed by the number of diseased coronary vessel segments. This structural hallmark provided a tangible link between protein expression patterns and the anatomical burden of disease.
Intriguingly, the investigators identified LDL receptor and PECAM1 among the proteins whose plasma levels bore a heightened relationship to the extent of coronary artery disease specifically in those with a hereditary risk. The LDL receptor is central to cholesterol homeostasis, mediating endocytosis of low-density lipoproteins, while PECAM1 plays a critical role in endothelial cell function and intercellular junction integrity. Their elevated presence may reflect a compensatory or pathological response within the vascular endothelium, potentiating atherosclerotic progression.
These findings suggest that hereditary atherosclerosis is characterized by a distinct, biologically coherent protein signature, offering new explanatory avenues for why certain individuals develop premature coronary artery disease despite engaging in heart-healthy behaviors. This biological pattern may redefine risk stratification, augmenting beyond traditional clinical metrics to encompass molecular diagnostics.
To unravel causality within these protein-disease associations, the research employed sophisticated genetic analyses, including Mendelian randomization techniques. This approach provided evidence implicating specific proteins—follistatin, PCSK9, and PECAM1—as not mere bystanders but active contributors to the pathogenesis of myocardial infarction. PCSK9, a well-known regulator of LDL receptor degradation, has already been targeted pharmacologically, validating the clinical relevance of these molecular insights.
The broader implications of this study extend into the realm of precision cardiovascular medicine. By delineating the molecular architectures linked to both hereditary and non-hereditary coronary artery disease, these insights lay groundwork for novel therapeutic targets and personalized risk prediction models. Future interventions might one day modulate these protein pathways to mitigate inherited susceptibility to atherosclerosis.
Clinical translation of these findings could revolutionize how cardiovascular risk is assessed, particularly in asymptomatic individuals with family histories suggestive of early-onset disease. Integrating plasma proteomics into routine cardiovascular screening could identify high-risk patients earlier, enabling timely preventive strategies that transcend lifestyle modification and standard pharmacotherapy.
Furthermore, this research highlights the importance of large-scale population studies like SCAPIS that combine comprehensive phenotyping with genetic and molecular analyses. Such integrative datasets empower researchers to disentangle complex disease etiologies and uncover subtle biological signals obscured in smaller cohorts.
The Karolinska Institutet-led study exemplifies collaborative innovation within modern biomedical research, uniting clinicians, geneticists, and molecular biologists to tackle the pressing public health challenge of coronary artery disease. By illuminating the molecular signature of hereditary risk, it opens a new vista for both mechanistic understanding and clinical management of cardiovascular disorders.
As the global burden of cardiovascular diseases continues to rise, identifying individuals genetically predisposed to early atherosclerosis assumes critical importance. This study’s demonstration of a specific plasma protein pattern heralds a paradigm shift toward molecularly informed cardiovascular risk assessment and intervention, promising to reduce the incidence of heart attacks and improve long-term outcomes.
In sum, the research presents compelling evidence that common proteins associated with inflammation, lipid metabolism, and vascular function form a distinct proteomic profile linked to inherited risk for early-onset coronary heart disease. These novel biomarkers, some causatively related to disease mechanisms, deepen our understanding of the biological underpinnings of atherosclerosis and pave the way for precision medicine approaches that can preempt clinical disease before irreversible arterial damage ensues.
Subject of Research: People
Article Title: Plasma Protein Profile Associated With a Family History of Early-Onset Coronary Heart Disease
News Publication Date: 7-Nov-2025
Web References:
https://www.ahajournals.org/doi/10.1161/CIRCGEN.124.005220
References:
Wahrenberg, A., Lind, L., Åberg, N., Häbel, H., Ström, M., Mälarstig, A., Magnusson, P.K.E., Halkola, R.-K., Bergström, G., Engström, G., Hagström, E., Jernberg, T., Söderberg, S., Östgren, C.J., Svensson, P. (2025). Plasma Protein Profile Associated With a Family History of Early-Onset Coronary Heart Disease. Circulation: Genomic and Precision Medicine. https://doi.org/10.1161/CIRCGEN.124.005220
Keywords: Cardiovascular disorders, hereditary atherosclerosis, plasma proteins, coronary heart disease, inflammation, lipid metabolism, proteomics, genetic risk, precision medicine
Tags: atherosclerosis molecular footprintcoronary artery disease biomarkersearly-onset coronary heart diseasefamilial cardiovascular eventsfollistatin and cathepsin Dgenetic predispositions to cardiovascular conditionshereditary risk factorsinflammatory pathways in heart diseaseinherited heart diseaselipid metabolism and heart healthplasma protein profileprecision medicine in heart disease
