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Science (New York, N.Y.) Nov 2021Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic...
Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries.
Topics: Aging; Alternative Splicing; Blood Proteins; COVID-19; Connective Tissue Diseases; Disease; Drug Development; Female; Gallstones; Genetic Association Studies; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomics; Humans; Internet; Male; Phenotype; Proteins; Proteome; Quantitative Trait Loci; Sex Characteristics
PubMed: 34648354
DOI: 10.1126/science.abj1541 -
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 -
International Journal of Molecular... Dec 2020Galectin-3 (Gal-3) is a β-galactoside-binding protein belonging to the lectin family with pleiotropic regulatory activities and several physiological cellular... (Review)
Review
Galectin-3 (Gal-3) is a β-galactoside-binding protein belonging to the lectin family with pleiotropic regulatory activities and several physiological cellular functions, such as cellular growth, proliferation, apoptosis, differentiation, cellular adhesion, and tissue repair. Inflammation, tissue fibrosis and angiogenesis are the main processes in which Gal-3 is involved. It is implicated in the pathogenesis of several diseases, including organ fibrosis, chronic inflammation, cancer, atherosclerosis and other cardiovascular diseases (CVDs). This review aims to explore the connections of Gal-3 with cardiovascular diseases since they represent a major cause of morbidity and mortality. We herein discuss the evidence on the pro-inflammatory role of Gal-3 in the atherogenic process as well as the association with plaque features linked to lesion stability. We report the biological role and molecular mechanisms of Gal-3 in other CVDs, highlighting its involvement in the development of cardiac fibrosis and impaired myocardium remodelling, resulting in heart failure and atrial fibrillation. The role of Gal-3 as a prognostic marker of heart failure is described together with possible diagnostic applications to other CVDs. Finally, we report the tentative use of Gal-3 inhibition as a therapeutic approach to prevent cardiac inflammation and fibrosis.
Topics: Animals; Biomarkers; Blood Proteins; Cardiovascular Diseases; Disease Models, Animal; Disease Susceptibility; Fibrosis; Galectins; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Molecular Targeted Therapy
PubMed: 33287402
DOI: 10.3390/ijms21239232 -
Nature Communications Jan 2022With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most...
With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.
Topics: Aged; Aged, 80 and over; Blood Proteins; Cohort Studies; Disease; Female; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Iceland; Male; Polymorphism, Single Nucleotide; Quantitative Trait Loci
PubMed: 35078996
DOI: 10.1038/s41467-021-27850-z -
Nature Chemical Biology Mar 2021Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular...
Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte and myeloid cell secretomes by direct purification of biotinylated secreted proteins from blood plasma. Our secretome dataset validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by the increased unconventional secretion of the cytosolic enzyme betaine-homocysteine S-methyltransferase (BHMT). This secretome profiling strategy enables dynamic and cell type-specific dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.
Topics: Animals; Betaine-Homocysteine S-Methyltransferase; Biotin; Biotinylation; Blood Proteins; Gene Expression; HEK293 Cells; Hepatocytes; Humans; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Muscle Cells; Myeloid Cells; Organ Specificity; Pericytes; Proteome; Proteomics; Staining and Labeling
PubMed: 33199915
DOI: 10.1038/s41589-020-00698-y -
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 -
BMC Genomics Aug 2022Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown.
BACKGROUND
Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown.
RESULTS
We aimed to identify circulating proteins causally associated with HF by leveraging genome-wide genetic association data for HF including 47,309 cases and 930,014 controls. We performed two-sample Mendelian randomization (MR) with multiple cis instruments as well as network and enrichment analysis using data from blood protein quantitative trait loci (pQTL) (2,965 blood proteins) measured in 3,301 individuals. Nineteen blood proteins were causally associated with HF, were not subject to reverse causality and were enriched in ligand-receptor and glycosylation molecules. Network pathway analysis of the blood proteins showed enrichment in NF-kappa B, TGF beta, lipid in atherosclerosis and fluid shear stress. Cross-phenotype analysis of HF identified genetic overlap with cardiovascular drugs, myocardial infarction, parental longevity and low-density cholesterol. Multi-trait MR identified causal associations between HF-associated blood proteins and cardiovascular outcomes. Multivariable MR showed that association of BAG3, MIF and APOA5 with HF were mediated by the blood pressure and coronary artery disease. According to the directional effect and biological action, 7 blood proteins are targets of existing drugs or are tractable for the development of novel therapeutics. Among the pathways, sialyl Lewis x and the activin type II receptor are potential druggable candidates.
CONCLUSIONS
Integrative MR analyses of the blood proteins identified causally-associated proteins with HF and revealed pleiotropy of the blood proteome with cardiovascular risk factors. Some of the proteins or pathway related mechanisms could be targeted as novel treatment approach in HF.
Topics: Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Blood Proteins; Heart Failure; Humans; Mendelian Randomization Analysis; Proteome; Risk Factors
PubMed: 35964012
DOI: 10.1186/s12864-022-08811-2 -
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 Metabolism Mar 2023Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify new disease processes. Here, we conducted a...
Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify new disease processes. Here, we conducted a cis-focused proteogenomic analysis of 2,923 plasma proteins measured in 1,180 individuals using antibody-based assays. We (1) identify 256 unreported protein quantitative trait loci (pQTL); (2) demonstrate shared genetic regulation of 224 cis-pQTLs with 575 specific health outcomes, revealing examples for notable metabolic diseases (such as gastrin-releasing peptide as a potential therapeutic target for type 2 diabetes); (3) improve causal gene assignment at 40% (n = 192) of overlapping risk loci; and (4) observe convergence of phenotypic consequences of cis-pQTLs and rare loss-of-function gene burden for 12 proteins, such as TIMD4 for lipoprotein metabolism. Our findings demonstrate the value of integrating complementary proteomic technologies with genomics even at moderate scale to identify new mediators of metabolic diseases with the potential for therapeutic interventions.
Topics: Humans; Proteogenomics; Proteomics; Diabetes Mellitus, Type 2; Quantitative Trait Loci; Blood Proteins
PubMed: 36823471
DOI: 10.1038/s42255-023-00753-7