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Nature Oct 2023The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we...
The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics.
Topics: Humans; ABO Blood-Group System; Biological Specimen Banks; Blood Proteins; COVID-19; Databases, Factual; Drug Discovery; Epistasis, Genetic; Fucosyltransferases; Genetic Predisposition to Disease; Genomics; Health; Plasma; Proprotein Convertase 9; Proteome; Proteomics; Public-Private Sector Partnerships; Quantitative Trait Loci; United Kingdom; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 37794186
DOI: 10.1038/s41586-023-06592-6 -
Cell Reports. Medicine Sep 2023We conduct proteome-wide Mendelian randomization and colocalization analyses to decipher the associations of blood proteins with the risk of type 2 diabetes and diabetic... (Meta-Analysis)
Meta-Analysis
We conduct proteome-wide Mendelian randomization and colocalization analyses to decipher the associations of blood proteins with the risk of type 2 diabetes and diabetic complications. Genetic data on plasma proteome are obtained from 54,306 UK Biobank participants and 35,559 Icelanders. Summary-level data on type 2 diabetes are obtained from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis consortium) consortium (74,124 cases) and FinnGen study (33,043 cases). Data on 10 diabetic complications are obtained from FinnGen and corresponding studies. Among 1,886 proteins, genetically predicted levels of 47 plasma proteins are associated with type 2 diabetes. Eleven of these proteins have strong support of colocalization. Seventeen proteins are associated with at least one diabetic complication, although a few have colocalization support. HLA-DRA, AGER, HSPA1A, and HSPA1B are associated with most microvascular complications. This study reveals causal proteins for the onset of type 2 diabetes and diabetic complications, which enhances the understanding of molecular etiology and development of therapeutics.
Topics: Humans; Diabetes Mellitus, Type 2; Proteome; Mendelian Randomization Analysis; Blood Proteins; Plasma
PubMed: 37652020
DOI: 10.1016/j.xcrm.2023.101174 -
Nature Immunology Jul 2023Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets....
Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.
Topics: Mice; Animals; Microglia; Multiomics; Blood-Brain Barrier; Alzheimer Disease; Fibrinogen
PubMed: 37291385
DOI: 10.1038/s41590-023-01522-0 -
Nature Communications Aug 2023The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of...
The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of targetable delivery vectors. Enveloped delivery modalities use viral envelope proteins, which determine tropism and induce membrane fusion. Here we develop DIRECTED (Delivery to Intended REcipient Cells Through Envelope Design), a modular platform that consists of separate fusion and targeting components. To achieve high modularity and programmable cell type specificity, we develop multiple strategies to recruit or immobilize antibodies on the viral envelope, including a chimeric antibody binding protein and a SNAP-tag enabling the use of antibodies or other proteins as targeting molecules. Moreover, we show that fusogens from multiple viral families are compatible with DIRECTED and that DIRECTED components can target multiple delivery chassis (e.g., lentivirus and MMLV gag) to specific cell types, including primary human T cells in PBMCs and whole blood.
Topics: Humans; Antibodies; Lentivirus; Membrane Fusion; Tropism; Viral Envelope Proteins
PubMed: 37612276
DOI: 10.1038/s41467-023-40788-8 -
Nature Oct 2023Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets. Because previous proteogenomic...
Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype-protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene-protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.
Topics: Humans; Alleles; Biological Specimen Banks; Biomarkers; Blood Proteins; Databases, Factual; Exome; Genetic Association Studies; Genomics; Hematopoiesis; Mutation; Plasma; Proteomics; United Kingdom
PubMed: 37794183
DOI: 10.1038/s41586-023-06547-x -
Nature Oct 2023High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge the gap between... (Comparative Study)
Comparative Study
High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge the gap between the genome and diseases. Here we performed association studies of Olink Explore 3072 data generated by the UK Biobank Pharma Proteomics Project on plasma samples from more than 50,000 UK Biobank participants with phenotypic and genotypic data, stratifying on British or Irish, African and South Asian ancestries. We compared the results with those of a SomaScan v4 study on plasma from 36,000 Icelandic people, for 1,514 of whom Olink data were also available. We found modest correlation between the two platforms. Although cis protein quantitative trait loci were detected for a similar absolute number of assays on the two platforms (2,101 on Olink versus 2,120 on SomaScan), the proportion of assays with such supporting evidence for assay performance was higher on the Olink platform (72% versus 43%). A considerable number of proteins had genomic associations that differed between the platforms. We provide examples where differences between platforms may influence conclusions drawn from the integration of protein levels with the study of diseases. We demonstrate how leveraging the diverse ancestries of participants in the UK Biobank helps to detect novel associations and refine genomic location. Our results show the value of the information provided by the two most commonly used high-throughput proteomics platforms and demonstrate the differences between them that at times provides useful complementarity.
Topics: Humans; Africa; Asia, Southern; Biological Specimen Banks; Blood Proteins; Datasets as Topic; Disease Susceptibility; Genome, Human; Genomics; Genotype; Iceland; Ireland; Phenotype; Plasma; Proteome; Proteomics; Quantitative Trait Loci; United Kingdom
PubMed: 37794188
DOI: 10.1038/s41586-023-06563-x -
Nature Communications Nov 2023Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an...
Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an important source for biomarker discovery but so far, few proteins have been identified with breast cancer risk. Here, we measure 2929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project to explore the association between protein levels, clinical characteristics, and gene variants, and to identify proteins with a causal role in breast cancer. We present 812 cis-acting protein quantitative trait loci for 737 proteins which are used as instruments in Mendelian randomisation analyses of breast cancer risk. Of those, we present five proteins (CD160, DNPH1, LAYN, LRRC37A2 and TLR1) that show a potential causal role in breast cancer risk with confirmatory results in independent cohorts. Our study suggests that these proteins should be further explored as biomarkers and potential drug targets in breast cancer.
Topics: Humans; Female; Breast Neoplasms; Biomarkers; Mammography; Phenotype; Blood Proteins; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Lectins, C-Type
PubMed: 37996402
DOI: 10.1038/s41467-023-43485-8 -
Nature Aging Sep 2023Platelet factors regulate wound healing and can signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central...
Platelet factors regulate wound healing and can signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.
Topics: Animals; Mice; Aging; Blood Coagulation Factors; Cognition; Longevity; Platelet Factor 4
PubMed: 37587231
DOI: 10.1038/s43587-023-00468-0 -
Journal of Thrombosis and Haemostasis :... Dec 2023Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is... (Review)
Review
Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is formed from its circulating precursor, plasminogen. Fibrin is by far the most legendary substrate, but plasmin is notoriously prolific and is known to cleave many other proteins and participate in the activation of other proteolytic systems. Fibrinolysis is often overshadowed by the coagulation system and viewed as a simplistic poorer relation. However, the primordial plasminogen activators evolved alongside the complement system, approximately 70 million years before coagulation saw the light of day. It is highly likely that the plasminogen activation system evolved with its roots in primordial immunity. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allow plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, numerous pathogens express their own plasminogen activators or contain surface proteins that provide binding sites for host plasminogen. The fibrinolytic system has been harnessed for clinical medicine for many decades with the development of thrombolytic drugs and antifibrinolytic agents. Our refined understanding and appreciation of the fibrinolytic system and its alliance with infection and immunity and beyond are paving the way for new developments and interest in novel therapeutics and applications. One must ponder as to whether the nomenclature of the system hampered our understanding, by focusing on fibrin, rather than the complex myriad of interactions and substrates of the plasminogen activation system.
Topics: Humans; Fibrinolysis; Fibrinolysin; Plasminogen Activators; Plasminogen; Fibrin; Serine Proteases
PubMed: 38000850
DOI: 10.1016/j.jtha.2023.09.012 -
EBioMedicine Jul 2023Individual plasma proteins have been identified as minimally invasive biomarkers for lung cancer diagnosis with potential utility in early detection. Plasma proteomes...
BACKGROUND
Individual plasma proteins have been identified as minimally invasive biomarkers for lung cancer diagnosis with potential utility in early detection. Plasma proteomes provide insight into contributing biological factors; we investigated their potential for future lung cancer prediction.
METHODS
The Olink® Explore-3072 platform quantitated 2941 proteins in 496 Liverpool Lung Project plasma samples, including 131 cases taken 1-10 years prior to diagnosis, 237 controls, and 90 subjects at multiple times. 1112 proteins significantly associated with haemolysis were excluded. Feature selection with bootstrapping identified differentially expressed proteins, subsequently modelled for lung cancer prediction and validated in UK Biobank data.
FINDINGS
For samples 1-3 years pre-diagnosis, 240 proteins were significantly different in cases; for 1-5 year samples, 117 of these and 150 further proteins were identified, mapping to significantly different pathways. Four machine learning algorithms gave median AUCs of 0.76-0.90 and 0.73-0.83 for the 1-3 year and 1-5 year proteins respectively. External validation gave AUCs of 0.75 (1-3 year) and 0.69 (1-5 year), with AUC 0.7 up to 12 years prior to diagnosis. The models were independent of age, smoking duration, cancer histology and the presence of COPD.
INTERPRETATION
The plasma proteome provides biomarkers which may be used to identify those at greatest risk of lung cancer. The proteins and the pathways are different when lung cancer is more imminent, indicating that both biomarkers of inherent risk and biomarkers associated with presence of early lung cancer may be identified.
FUNDING
Janssen Pharmaceuticals Research Collaboration Award; Roy Castle Lung Cancer Foundation.
Topics: Humans; Biomarkers, Tumor; Early Detection of Cancer; Lung Neoplasms; Biomarkers; Blood Proteins; Smoking; Proteome
PubMed: 37379654
DOI: 10.1016/j.ebiom.2023.104686