Proven miniaturization technology to bolster high-throughput protein biomarker discovery

Sun et al. (2023) Plasma proteomic associations with genetics and health in the UK Biobank. Nature, DOI: 10.1038/s41586-023-06592-600

The largest proteomic study conducted to date (over 54,000 UK Biobank participants) by the Pharma Proteomics Project reveals biological insights into proteomic disease signatures, and prediction models for demographic and health indicators. The results not only validated several established proteomic associations, but also uncovered 4,287 pQTLs (protein quantitative trait loci), 81% of which are novel genetic associations with protein levels that have not been previously reported.

Dhindsa et al. (2023) Rare variant associations with plasma protein levels in the UK Biobank. Nature, DOI: 10.1038/s41586-023-06547-x

An extensive rare variant proteogenomics study by AstraZeneca Genomics Initiative included 2,923 plasma protein abundances measured in 49,736 UK Biobank human exomes. The paper highlights several examples of how this protein-coding pQTL atlas can address drug discovery and clinical pipeline challenges. It is anticipated that this resource will provide novel insights into protein regulatory networks, upstream trans regulators of target genes whose inhibition could increase target protein levels, target safety assessments and drug repositioning opportunities.

Álvez et al. (2023) Next generation pan-cancer blood proteome profiling using proximity extension assay. Nat Commun, DOI: 10.1038/s41467-023-39765-y

The paper describes a strategy for cost-effective pan-cancer analysis of blood protein profiles with the goal to allow simultaneous identification of cancers using only a few microliters of blood. This approach combined with machine learning and traditional cancer screening procedures could facilitate the discovery of cancers early, and thus help clinicians to start treatment of cancer patients at earlier stages.

Sveinbjornsson et al. (2022) Multiomics study of nonalcoholic fatty liver disease. Nat Genet, DOI: 10.1038/s41588-022-01199-5

Integration of genome-wide association study of non-alcoholic fatty liver, cirrhosis and hepatocellular carcinoma with gene expression and proteomic data identifies new sequence variants, putative casual genes and multiple proteins involved in liver disease pathogenesis, underscoring them as potential drug targets. The study highlights the potential of measurement of plasma proteins to serve as a non-invasive tool for use in the diagnosis and monitoring of disease.

Zannad et al. (2022) Effect of a sodium-glucose cotransporter-2 (SGLT2) inhibitor on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme. European Heart Journal, DOI: 10.1093/eurheartj/ehac495

The EMPEROR studies (Phase 3, randomized, double-blind trials) were conducted in patients with and without diabetes, and investigated effect of a sodium-glucose cotransporter-2 (SGLT2) inhibitor on the circulating levels of intracellular proteins in patients with chronic heart failure. The results of this large-scale proteomics study show that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.

Filbin et al. (2021) Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions. Cell Reports Medicine, DOI: 10.1016/j.xcrm.2021.100287

By leveraging protein signatures with scRNA-seq datasets from PBMCs of COVID-19 patients and from healthy tissues, researchers identified over 257 proteins independently associated with COVID-19 severity at day zero and over 700 proteins at day three and seven. “This work lays the foundation for understanding how the plasma proteome can be leveraged to gain insights into underlying disease pathways and potential therapeutic targets, and to develop diagnostics that can be used to stratify high-risk patients as candidates for tailored therapies and earlier interventions.”