Klasar próteina í sermi tengja erfðir við sjúkdóm - verkefni lokið

Fréttatilkynning verkefnisstjóra

30.5.2022

Þrátt fyrir að rannsóknir hafi staðið yfir í marga áratugi sem benda til þess að þættir í blóðinu (og blóðvökvanum) séu mikilvægir fyrir aldurstengda sjúkdómsferla og fylgikvilla þeirra, hefur ítarleg greining á próteinum í blóðinu ekki átt sér stað vegna tæknilegra örðugleika við mælingu á þeim. Nýlegar framfarir við próteinmælingar hafa gert kleift að mæla þúsundir próteina í stóru rannsóknarþýði í einu blóðsýni, sem leitt hefur í ljós að samsetning próteina í blóðinu er mjög flókin. Í þessari rannsókn var magn 4872 próteina, sem nær yfir stóran hluta utanfrumupróteina, í sermi 5457 einstaklinga úr öldrunarrannsókn AGES Reykjavik ákvarðað í tengslum við stjórnun þeirra, innbyrðis samskipta próteinanna, og tengsl þeirra við erfðaþætti og algenga sjúkdóma af ólíkum vefjafræðilegum uppruna, auk breytinga yfir tíma. Helstu niðurstöður úr rannsókn okkar eru teknar saman hér að neðan; próteinin í serminu greinast í aðskilda klasa sem innihalda prótein framleidd í nánast öllum vefjum líkamanans; erfðaþættir stjórna þúsundum einstakra próteina og tengdum próteinklösum; erfðaþættir sem stjórna próteinum í sermi virðast einnig vera áhættuþættir fyrir marga langvarandi sjúkdóma sem eru ólíkir hvað varðar vefjauppruna og undirliggjandi meinferla.

English:

Decades of research has demonstrated that circulating factors are important for age-related disease processes and complications, however, a comprehensive analysis of the serum proteome has remained unexplored due to technical constraints. Recent advances in proteomic technology have enabled simultaneous measurements of thousands of proteins in large population studies, revealing the depth and complexity of the serum proteome. In the current study, the levels of 4872 proteins covering the majority of predicted extracellular proteins in the serum of 5457 subjects from the AGES Reykjavik cohort were measured for their co-regulation behaviours, links to genetics and many diseases of different aetiologies, as well as changes over time. Our main findings are summarized below: The serum proteome is organized into discrete modules composed of proteins synthesized from any tissue in the body; genetic markers are linked to thousands of individual serum proteins and their associated networks; and these genetic markers share genetic risk factors with many common diseases of various aetiologies.

Information on how the results will be applied
Human serum contains a dynamic flux of proteins that involves the majority, if not all, of the body's tissues and cells. We have found a strong link between individual proteins and protein networks in circulation to a variety of common diseases with diverse aetiologies. This implies that the serum proteome is a rich and easily accessible resource for identifying biomarkers and drug targets for almost any disease. IHA scientists are continuing to expand on this knowledge to develop new biomarkers and drug targets for complex diseases. In a recent publication by the current project's principal investigator, it is discussed how the use of this information in routine clinical evaluations may transform the future practice of medicine (PMID: 32988739).

• A list of the project’s outputs
Several papers have been published, many in high-impact journals, as listed below. This includes the publication of summary statistics data for each measured protein to the GWAS catalogue database (https://doi.org/10.5281/zenodo.5711426), as well as the accession IDs detailed in Supplementary Data 16 in Gudjonsson et al., Nature Communications 2022 (Open access). These data, which we have made public, will be a valuable resource for the scientific community as well as for our team.

Publications listed in chronological order (from 2018)
1. Adrienne, T. et al. Proteomic analysis identifies circulating proteins associated with plasma amyloid βeta and incident dementia. Biological Psychiatry (under review) (2022)
2. Axelsson, G.T. et al., The Proteomic Profile of Interstitial Lung Abnormalities. American Journal of Respiratory and Critical Care Medicine, 2nd revision (2022)
3. Gudjonsson, A., et al. A genome-wide association study of serum proteins reveals shared loci with common diseases. Nature Communications 13, 1-13 (2022).
4. Emilsson, V., et al. Coding and regulatory variants are associated with serum protein levels and
disease. Nature Communications 13, 1-11 (2022).
5. Walker, K.A., et al. Large-scale plasma proteomic analysis identifies proteins and pathways
associated with dementia risk. Nature Aging 1, 473-489 (2021).
6. Salazar, M.G., et al. Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated
energy expenditure at thermoneutrality. bioRxiv (2021). Journal of Clinical Investigation, 2nd
review (2022)
7. Lamb, J.R., Jennings, L.L., Gudmundsdottir, V., Gudnason, V. & Emilsson, V. It’s in our blood: a
glimpse of personalized medicine. Trends in Molecular Medicine 27, 20-30 (2021).
8. Anisul, M., et al. A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited
host targets of clinical relevance. Elife 10(2021).
9. Emilsson, V., et al. A Proteogenomic Signature of Age-related Macular Degeneration in Blood.
medRxiv (2021). Nature Communications, in 2nd review (2022)
10. Emilsson, V., et al. Serum levels of ACE2 are higher in patients with obesity and diabetes. Obesity Science & Practice 7, 239-243 (2021).
11. Kellogg, G., et al. Molecular screening of familial hypercholesterolemia in Icelanders. Scandinavian Journal of Clinical and Laboratory Investigation 80, 508-514 (2020).
12. Gudmundsdottir, V., et al. Circulating protein signatures and causal candidates for type 2 diabetes. Diabetes 69, 1843-1853 (2020).
13. Emilsson, V., et al. Antihypertensive medication uses and serum ACE2 levels: ACEIs/ARBs
treatment does not raise serum levels of ACE2. medRxiv (2020).
14. Linnér, R.K., et al. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nature genetics 51, 245-257 (2019).
15. Keulen, D.v., et al. Oncostatin M reduces atherosclerosis development in APOE* 3Leiden. CETP
mice and is associated with increased survival probability in humans. PloS one 14, e0221477
(2019). 14. Emilsson, V., Gudnason, V. & Jennings, L.L. Predicting health and life span with the deep
plasma proteome. Nature medicine 25, 1815-1816 (2019).
16. Emilsson, V., et al. Co-regulatory networks of human serum proteins link genetics to disease.
Science 361, 769-773 (2018).
17. Aldi, S., et al. Integrated human evaluation of the lysophosphatidic acid pathway as a novel
therapeutic target in atherosclerosis. Molecular Therapy-Methods & Clinical Development 10, 17-
28 (2018).

Heiti verkefnis: Klasar próteina í sermi tengja erfðir við sjúkdóm / Protein networks in circulation link genetics to disease
Verkefnisstjóri: Valur Emilsson, Hjartavernd
Tegund styrks: Verkefnisstyrkur
Styrktímabil: 2019-2021
Fjárhæð styrks: 51,870 millj. kr. alls
Tilvísunarnúmer Rannís: 195761