Cartilage Acidic Protein 1 in Plasma Associates With Prevalent Osteoarthritis and Predicts Future Risk as Well as Progression to Joint Replacements: Results From the UK Biobank Resource DOI Creative Commons
Unnur Styrkársdóttir, Sigrún H. Lund, Guðmar Þorleifsson

et al.

Arthritis & Rheumatology, Journal Year: 2022, Volume and Issue: 75(4), P. 544 - 552

Published: Oct. 14, 2022

Objective The level of cartilage acidic protein 1 (CRTAC1) in plasma was recently discovered to be associated with osteoarthritis (OA) risk and progression joint replacement Iceland. This study undertaken validate these findings an independent population. Methods In this study, 1,462 proteins were measured 54,265 participants from the UK Biobank on Olink Explore platform. We analyzed association prevalent OA, incident replacement. assessed specificity OA through comparison associations inflammatory diseases previous Results CRTAC1 showed strongest knee (odds ratio [OR] 1.34 [95% confidence interval (95% CI) 1.27, 1.41]) hip (OR 1.19 CI 1.11, 1.28]). It predicted diagnosis (hazard [HR] 1.40 1.35, 1.46]) (HR 1.25 1.19, 1.31]), as well 1.20 1.08, 1.33] for HR 1.22 1.38] hip), while no found diseases. Individuals highest quintile based level, age, sex, body mass index had a 10‐fold or within 5 years compared those lowest quintile. Adding aggrecan core (ACAN) neurocan (NCAN) model improved prediction but not Furthermore, we replicated CUB domain–containing prior Conclusion Plasma is specific biomarker predictor ACAN NCAN levels OA.

Language: Английский

Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome DOI Creative Commons
Jing Sun, Jianhui Zhao, Fangyuan Jiang

et al.

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: Sept. 19, 2023

Abstract Background The proteome is a major source of therapeutic targets. We conducted proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and targets for colorectal cancer (CRC). Methods Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, summary-level data extracted 4853 circulating markers. Genetic associations with CRC obtained large-scale GWAS meta-analysis (16,871 cases 26,328 controls), the FinnGen cohort (4957 304,197 UK Biobank (9276 477,069 controls). Colocalization summary-data-based MR (SMR) analyses performed sequentially verify causal role proteins. Single cell-type expression analysis, protein-protein interaction (PPI), druggability evaluation further detect specific cell type enrichment prioritize potential Results Collectively, genetically predicted levels 13 proteins associated risk. Elevated two (GREM1, CHRDL2) decreased 11 an increased risk CRC, among which four CLSTN3, CSF2RA, CD86) prioritized most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial monocytes colon tumor tissue. Two interactive pairs (GREM1 CHRDL2; MMP2 TIMP2) identified be involved osteoclast differentiation tumorigenesis pathways; (POLR2F, CD86, MMP2) have been targeted drug development autoimmune diseases other cancers, potentials being repurposed as CRC. Conclusions This several biomarkers provided new insights into etiology promising screening drugs

Language: Английский

Citations

88
Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses DOI Creative Commons
Shuai Yuan,

Fengzhe Xu,

Xue Li

et al.

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(9), P. 101174 - 101174

Published: Aug. 30, 2023

We conduct proteome-wide Mendelian randomization and colocalization analyses to decipher the associations of blood proteins with risk type 2 diabetes diabetic complications. Genetic data on plasma proteome are obtained from 54,306 UK Biobank participants 35,559 Icelanders. Summary-level DIAGRAM (DIAbetes Genetics Replication And Meta-analysis consortium) consortium (74,124 cases) FinnGen study (33,043 cases). Data 10 complications corresponding studies. Among 1,886 proteins, genetically predicted levels 47 associated diabetes. Eleven these have strong support colocalization. Seventeen at least one complication, although a few support. HLA-DRA, AGER, HSPA1A, HSPA1B most microvascular This reveals causal for onset complications, which enhances understanding molecular etiology development therapeutics.

Language: Английский

Citations

62
Molecular quantitative trait loci DOI
François Aguet, Kaur Alasoo, Yang Li

et al.

Nature Reviews Methods Primers, Journal Year: 2023, Volume and Issue: 3(1)

Published: Jan. 25, 2023

Language: Английский

Citations

52
Plasma protein biomarkers for early prediction of lung cancer DOI Creative Commons
Michael Davies, Takahiro Sato, Haitham Ashoor

et al.

EBioMedicine, Journal Year: 2023, Volume and Issue: 93, P. 104686 - 104686

Published: June 26, 2023

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 future prediction.The Olink® Explore-3072 platform quantitated 2941 496 Liverpool Lung Project samples, including 131 cases taken 1-10 years prior to diagnosis, 237 controls, and 90 subjects at multiple times. 1112 significantly associated haemolysis were excluded. Feature selection bootstrapping differentially expressed proteins, subsequently modelled prediction validated UK Biobank data.For samples 1-3 pre-diagnosis, 240 different cases; 1-5 year 117 of these 150 further identified, mapping pathways. Four machine learning algorithms gave median AUCs 0.76-0.90 0.73-0.83 the respectively. External validation 0.75 (1-3 year) 0.69 (1-5 year), AUC 0.7 up 12 diagnosis. The models independent age, smoking duration, histology presence COPD.The proteome provides which may be used identify those greatest risk cancer. pathways are when is more imminent, indicating that both inherent identified.Janssen Pharmaceuticals Research Collaboration Award; Roy Castle Cancer Foundation.

Language: Английский

Citations

46
Genetic associations with ratios between protein levels detect new pQTLs and reveal protein-protein interactions DOI Creative Commons
Karsten Suhre

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(3), P. 100506 - 100506

Published: Feb. 26, 2024

Protein quantitative trait loci (pQTLs) are an invaluable source of information for drug target development because they provide genetic evidence to support protein function, suggest relationships between cis- and trans-associated proteins, link proteins disease endpoints. Using Olink proteomics data 1,463 measured in over 54,000 samples the UK Biobank, we identified 4,248 associations with 2,821 ratios levels (rQTLs). rQTLs were 7.6-fold enriched known protein-protein interactions, suggesting that their reflect biological links implicated proteins. Conducting a GWAS on increased number discovered signals by 24.7%. The approach can identify novel clinical relevance, causal gene identification, reveal complex networks interacting Taken together, our study adds significant value insights be derived from UKB motivates wider use large-scale GWAS.

Language: Английский

Citations

17
The 2022 Report on the Human Proteome from the HUPO Human Proteome Project DOI
Gilbert S. Omenn, Lydie Lane, Christopher M. Overall

et al.

Journal of Proteome Research, Journal Year: 2022, Volume and Issue: 22(4), P. 1024 - 1042

Published: Nov. 1, 2022

The 2022 Metrics of the Human Proteome from HUPO Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18 407 (93.2%) 19 750 predicted proteins coded in human genome, a net gain 50 since 2021 data sets generated around world and reanalyzed by HPP. Conversely, number neXtProt PE2, PE3, PE4 missing reduced 78 1421 to 1343. This represents continuing experimental progress on proteome parts list across all chromosomes, as well significant reclassifications. Meanwhile, applying proteomics vast array biological clinical studies continues yield findings growing integration with other omics platforms. We present highlights Chromosome-Centric HPP, Biology Disease-driven HPP Resource Pillars, compare features mass spectrometry Olink Somalogic platforms, note emergence translation products ribosome profiling small open reading frames, discuss launch initial Grand Challenge Project, "A Function Each Protein".

Language: Английский

Citations

48
Quantitative protein biomarker panels: a path to improved clinical practice through proteomics DOI Creative Commons
Johannes Hartl, Florian Kurth, Kai Kappert

et al.

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 15(4)

Published: March 20, 2023

The utilisation of protein biomarker panels, rather than individual biomarkers, offers a more comprehensive representation human physiology. It thus has the potential to improve diagnosis, prognosis and differentiation responders from nonresponders in context precision medicine. Although several proteomic techniques exist for measuring integration proteomics into clinical practice been limited. In this Commentary, we highlight significance quantitative panels medicine outline challenges that must be addressed order identify most promising implement them routines realise their medical potential. Furthermore, argue absolute quantification through targeted mass spectrometric assays remains technology translating routine applications due its high flexibility, low sample costs, independence affinity reagents entry barriers existing laboratory workflows.

Language: Английский

Citations

27
Proteogenomic links to human metabolic diseases DOI
Mine Koprulu, Julia Carrasco-Zanini, Eleanor Wheeler

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(3), P. 516 - 528

Published: Feb. 23, 2023

Language: Английский

Citations

26
Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease DOI Creative Commons
Carlos Cruchaga, Daniel Western, Jigyasha Timsina

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: June 9, 2023

The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes disease-associated loci. QTL mapping mainly been focused on multi-tissue expression or plasma protein (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs which 1,585 are unique to CSF, demonstrating genetic regulation CSF proteome. In addition established chr6p22.2-21.32 HLA region, pleiotropic regions chr3q28 near

Language: Английский

Citations

26
Plasma Proteomics to Identify Drug Targets for Ischemic Heart Disease DOI Creative Commons
Mohsen Mazidi, Neil Wright, Pang Yao

et al.

Journal of the American College of Cardiology, Journal Year: 2023, Volume and Issue: 82(20), P. 1906 - 1920

Published: Nov. 1, 2023

Integrated analyses of plasma proteomic and genetic markers in prospective studies can clarify the causal relevance proteins discover novel targets for ischemic heart disease (IHD) other diseases.

Language: Английский

Citations

23