Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression

Szilágyi, I; Vallerga, Costanza L.; Boer, Cindy G.; Schiphof, D.; Ikram, M. Arfan; Bierma-Zeinstra, Sita M A; Meurs, Joyce B. J. van

doi:10.1093/rheumatology/keac415

Cited by 28 publications

(14 citation statements)

References 43 publications

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“…The strong replication of the association of CRTAC1 with OA shows that the Olink Explore and SomaScan affinity-based platforms measure CRTAC1 in a similar manner. We had previously also shown a high correlation between CRTAC1 levels in the SomaScan and Olink Target assays (1), and recently, CRTAC1 was confirmed as a biomarker for OA severity and progression using the Olink Target assay (6). Furthermore, CRTAC1 was recently found to be a potential OA biomarker candidate using a mass spectrometry platform (8).…”

Section: Discussionmentioning

confidence: 91%

“…Lack of replication in an independent sample set was a limitation of our previous study (1), but replications in other populations of various ethnicities as well as further technical validations are needed before further implementation of a disease biomarker. Recently, a study in the Rotterdam cohort confirmed CRTAC1 as a biomarker for OA severity and progression (6).…”

Section: Introductionmentioning

confidence: 98%

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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

Styrkársdóttir

Lund

Þorleifsson

et al. 2022

Arthritis & Rheumatology

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

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 98%

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

Styrkársdóttir

Lund

Þorleifsson

et al. 2022

Arthritis & Rheumatology

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“…We found no correlations between CRTAC1 concentrations and the domains of the SF-36 health survey. Determination of the reasons behind and significance of decreased CRTAC1 concentration in a subset of post-COVID-19 patients will require more detailed analysis of the roles of age, nature, and timing of the episode of COVID-19, and conditions that drive plasma CRTAC1 concentration up, such as osteoarthritis (Styrkarsdottir et al, 2021(Styrkarsdottir et al, , 2023Szilagyi et al, 2023;Tardif et al, 2022), or down, such idiopathic pulmonary fibrosis (Mayr et al, 2021) or COPD (this study). Importantly, longitudinal studies of CRTAC1 concentrations are needed post-COVID-19 in patients with and without symptoms of long COVID.…”

Section: Discussionmentioning

confidence: 99%

Decreased plasma cartilage acidic protein 1 in COVID‐19

Johansson,

Balnis,

Muehlbauer

et al. 2023

Physiological Reports

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Cartilage acidic protein‐1 (CRTAC1) is produced by several cell types, including Type 2 alveolar epithelial (T2AE) cells that are targeted by SARS‐CoV2. Plasma CRTAC1 is known based on proteomic surveys to be low in patients with severe COVID‐19. Using an ELISA, we found that patients treated for COVID‐19 in an ICU almost uniformly had plasma concentrations of CRTAC1 below those of healthy controls. Magnitude of decrease in CRTAC1 distinguished COVID‐19 from other causes of acute respiratory decompensation and correlated with established metrics of COVID‐19 severity. CRTAC1 concentrations below those of controls were found in some patients a year after hospitalization with COVID‐19, long COVID after less severe COVID‐19, or chronic obstructive pulmonary disease. Decreases in CRTAC1 in severe COVID‐19 correlated (r = 0.37, p = 0.0001) with decreases in CFP (properdin), which interacts with CRTAC1. Thus, decreases of CRTAC1 associated with severe COVID‐19 may result from loss of production by T2AE cells or co‐depletion with CFP. Determination of significance of and reasons behind decreased CRTAC1 concentration in a subset of patients with long COVID will require analysis of roles of preexisting lung disease, impact of prior acute COVID‐19, age, and other confounding variables in a larger number of patients.

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“…Sample-based Quality Control (QC) of the proteomics data was done as published [17] based on Olink-reported QC warnings, that is, samples that deviate > ± 0.3 NPX from the plate median. In this study, there were a total of 76 QC warnings.…”

Section: Assessment Of Plasma Proteomic Profilingmentioning

confidence: 99%

Plasma proteomic signature of fatty liver disease: The Rotterdam Study

et al. 2023

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Background and Aims: Fatty liver disease (FLD) is caused by excess fat in the liver, and its global prevalence exceeds 33%. The role of protein expression on the pathogenesis of FLD and accompanied fibrosis and its potential as a disease biomarker is currently not clear. Hence, we aimed to identify plasma proteomics associated with FLD and fibrosis using population-based data. Approach and Results: Blood samples were collected from 2578 participants from the population-based Rotterdam Study cohort. The proximity extension assay reliably measured plasma levels of 171 cardiometabolic and inflammatory-related proteins (Olink Proteomics). FLD was assessed by ultrasound, and fibrosis by transient elastography. Logistic regression models quantified the association of plasma proteomics with FLD and fibrosis. In addition, we aimed to validate our results in liver organoids. The cross-sectional analysis identified 27 proteins significantly associated with FLD surpassing the Bonferroni-corrected p<2.92×10−4. The strongest association was observed for FGF-21 (β=0.45, p=1.07×10−18) and carboxylesterase 1 (CES1) protein (β=0.66, p=4.91×10−40). Importantly, 15 of the 27 proteins significantly associated with FLD were also associated with liver fibrosis. Finally, consistent with plasma proteomic profiling, we found the expression levels of IL-18 receptor 1 (IL-18R1) and CES1 to be upregulated in an FLD model of 3-dimensional culture human liver organoids. Conclusions: Among the general population, several inflammatory and cardiometabolic plasma proteins were associated with FLD and fibrosis. Particularly, plasma levels of FGF-21, IL-18R1, and CES1 were largely dependent on the presence of FLD and fibrosis and may therefore be important in their pathogenesis.

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Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression

Cited by 28 publications

References 43 publications

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

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

Decreased plasma cartilage acidic protein 1 in COVID‐19

Plasma proteomic signature of fatty liver disease: The Rotterdam Study

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