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Dissecting the human plasma proteome and inflammatory response biomarkers.

ABSTRACT: A central focus of clinical proteomics is to search for biomarkers in plasma for diagnostic and therapeutic use. We studied a set of plasma proteins accessed from the Healthy Human Individual's Integrated Plasma Proteome (HIP(2)) database, a larger set of curated human proteins, and a subset of inflammatory proteins, for overlap with sets of known protein biomarkers, drug targets, and secreted proteins. Most inflammatory proteins were found to occur in plasma, and over three times the level of biomarkers were found in inflammatory plasma proteins and their interacting protein neighbors compared to the sets of plasma and curated human proteins. Percentage overlaps with Gene Ontology terms were similar between the curated human set and plasma protein set, yet the set of inflammatory plasma proteins had a distinct ontology-based profile. Most of the major hub proteins within protein-protein interaction networks of tissue-specific sets of inflammatory proteins were found to occur in disease pathways. The present study presents a systematic approach for profiling a plasma subproteome's relationship to both its potential range of clinical application and its overlap with complex disease.

SUBMITTER: Saha S

PROVIDER: S-EPMC3402908 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Dissecting the human plasma proteome and inflammatory response biomarkers.

Saha Sudipto S Harrison Scott H SH Chen Jake Yue JY

Proteomics 20090101 2

A central focus of clinical proteomics is to search for biomarkers in plasma for diagnostic and therapeutic use. We studied a set of plasma proteins accessed from the Healthy Human Individual's Integrated Plasma Proteome (HIP(2)) database, a larger set of curated human proteins, and a subset of inflammatory proteins, for overlap with sets of known protein biomarkers, drug targets, and secreted proteins. Most inflammatory proteins were found to occur in plasma, and over three times the level of b ...[more]

PMID: 19105179

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Project description:Inflammation is a condition stemming from complex host defense and tissue repair mechanisms, often simply characterized by plasma levels of a single acute reactant. We attempted to identify candidate biomarkers of systemic inflammation within the plasma proteome. We applied quantitative proteomics using isobaric mass tags (iTRAQ) tandem mass spectrometry to quantify proteins in plasma of 500 Nepalese children 6-8 years of age. We evaluated those that co-vary with inflammation, indexed by ?-1-acid glycoprotein (AGP), a conventional biomarker of inflammation in population studies. Among 982 proteins quantified in >10% of samples, 99 were strongly associated with AGP at a family-wise error rate of 0.1%. Magnitude and significance of association varied more among proteins positively (n = 41) than negatively associated (n = 58) with AGP. The former included known positive acute phase proteins including C-reactive protein, serum amyloid A, complement components, protease inhibitors, transport proteins with anti-oxidative activity, and numerous unexpected intracellular signaling molecules. Negatively associated proteins exhibited distinct differences in abundance between secretory hepatic proteins involved in transporting or binding lipids, micronutrients (vitamin A and calcium), growth factors and sex hormones, and proteins of largely extra-hepatic origin involved in the formation and metabolic regulation of extracellular matrix. With the same analytical approach and the significance threshold, seventy-two out of the 99 proteins were commonly associated with CRP, an established biomarker of inflammation, suggesting the validity of the identified proteins. Our findings have revealed a vast plasma proteome within a free-living population of children that comprise functional biomarkers of homeostatic and induced host defense, nutrient metabolism and tissue repair, representing a set of plasma proteins that may be used to assess dynamics and extent of inflammation for future clinical and public health application.

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

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Dissecting the human plasma proteome and inflammatory response biomarkers.

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Dissecting the human plasma proteome and inflammatory response biomarkers.

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