Trends in Molecular Medicine
OpinionIt’s in Our Blood: A Glimpse of Personalized Medicine
Section snippets
Challenges and Prospects of Personalized Medicine
Despite personalized medicine (see Glossary) being featured prominently in industry and academia, its promise has largely not been realized. There have been some notable successes, particularly in oncology [1., 2., 3.] and often involving genetic variants in the target of a candidate therapy. However, patients in clinical practice are generally not prescribed therapeutics based on an individual´s higher probability of an effective response. There are many reasons for this lack of progress, but
Serum Proteins in Coregulatory Networks Associate with Disease
The cardiovascular system controls appropriate blood flow to and from all tissues of the body to maintain global homeostasis in terms of physiological temperature, oxygen transport, and exchange of nutrients and waste [12]. Tissues and organs contribute components and capabilities to the whole organism by systemic coordination. How is higher order coordination across different tissues achieved? In addition to the nervous and lymphatic systems, blood is well placed to facilitate such
Cross-Tissue Regulation of Serum Protein Networks
What then might be the function of the serum protein networks and how do they arise? A significant clue comes from the analysis of protein quantitative trait loci (pQTLs) (Box 2), where variation of proteins in blood and genetic variation in the same population were compared [4,11,27,28]. These analyses showed that serum proteins were frequently under genetic control individually and also at the level of protein networks [4]. This is where a genetic variant controlled a protein encoded by a
Serum Protein Networks Link Genetics to Disease
The many large-scale genome-wide association studies (GWASs) over the past decade have documented >70 000 DNA variants associated with phenotypes related to complex disease [41]. These analyses revealed that each complex disease trait is associated with hundreds of risk loci of small effect sizes and commonly located outside coding regions (e.g., reviewed in [42]). Integration of intermediate traits, such as mRNA and/or protein levels, with genetics and disease traits aids in the identification
Serum Proteins and Holistic Molecular Medicine
Many approaches to biomarker development have been reported, including, for instance, measurement of RNAs, metabolites, peptides, and volatile organic compounds from various sources and associating such measures with clinically relevant phenotypes [50., 51., 52., 53., 54., 55., 56., 57.]. The increasing availability of genome-scale omics data and the parallel development of computational tools have allowed effective integration of the high-dimensional data at the level of molecular networks [24,
Serum Protein-Based Biomarker Platform: The Realization of Personalized Medicine
What might be the consequences of being able to routinely assess the holistic disease state of individuals? One obvious benefit will be comprehensive clinical assessments and early diagnoses. Shifting diagnoses toward an objective numeric test will provide the patient and doctor a glimpse into the future and potentially avoid missed diagnoses (Figure 4). A serum protein-based platform would inform on many diseases for the individual tested and, therefore, would provide a richness and depth that
Concluding Remarks
Much more remains to be discovered and tested, including qualification of validated biomarkers based on selected proteins, further exploration of serum protein based genetic and drug signatures, application to rare diseases, infectious diseases, and different environmental and ethnic backgrounds (see Outstanding Questions). However, at this point, it does appear that serum proteins exist in coregulatory networks spanning all tissues of the body, the protein levels are under genetic control, and
Acknowledgments
V.E. and Va.G. are supported by the Icelandic Research Fund (IRF grants 195761-051 and 184845-053).
Disclaimer Statement
J.R.L. was, and L.L.J. is, an employee of, and own stocks in, Novartis.
Glossary
- Biomarker
- a biological entity that can be measured and optimally quantified and that expresses the effect of exposure, condition, or disease.
- Coregulatory network module
- a cluster of proteins coregulated or covarying across individuals. The covariance profile may be determined by coregulation at the transcriptional level and/or post-transcriptional coregulatory mechanisms, including, for instance, protein maturation, secretion, clearance, and stability.
- Disease
- a medical condition of the organism or
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