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Identification and validation of ECM1 as a causal plasma biomarker in knee osteoarthritis through proteome-wide
Huadong Wang1,2, Yinhui Yao2, Xuelian Yin2
1Chengde Medical University, Chengde, China.
Abstract:
Knee osteoarthritis (KOA) is a degenerative joint disease with a genetic component. Nonetheless, it remains largely unknown how risk variants influence the OA risk through their effects on proteins. This study aimed to identify new and effective drug targets for the diagnosis of KOA. A proteome-wide association study was conducted using summary datasets from genome-wide association studies of OA and protein quantitative trait locus data. The Gene Expression Omnibus dataset GSE63359 was used to identify differentially expressed genes between controls and KOA. Subsequently, Mendelian randomization and colocalization analyses were performed on the intersecting proteins identified using the aforementioned methods to assess the association between protein levels and KOA risk. Clinical samples were included, and RT-qPCR and enzyme-linked immunosorbent assay were used to validate the expression of risk proteins between the KOA and control groups. Extracellular matrix protein 1 (ECM1) expression was causally related to KOA. Further support from colocalization analysis suggested that ECM1 might serve as a potential drug target for KOA. Validation of clinical samples indicated that ECM1 levels were higher in the KOA group than in the control group and that ECM1 demonstrated significant diagnostic efficacy for KOA (area under the curve = 0.85). This study identified ECM1 as a risk factor for the pathogenesis of KOA and showed promising therapeutic targets for KOA treatment.
Insights
Extracellular matrix protein 1 (ECM1) is causally linked to knee osteoarthritis (KOA) risk. Elevated ECM1 levels in KOA patients suggest it
Area of Science:
- Genetics and Molecular Biology
- Rheumatology
- Biochemistry
Background:
- Knee osteoarthritis (KOA) is a prevalent degenerative joint disease with a known genetic influence.
- The precise mechanisms by which genetic risk variants impact KOA pathogenesis via protein alterations remain largely unelucidated.
- Identifying novel therapeutic targets is crucial for improving KOA diagnosis and treatment.
Purpose of the Study:
- To identify novel drug targets for knee osteoarthritis (KOA) diagnosis and treatment.
- To investigate the causal relationship between protein expression and KOA risk.
- To validate potential protein biomarkers in clinical samples.
Main Methods:
- Proteome-wide association study (PWAS) integrating genome-wide association study (GWAS) and protein quantitative trait loci (pQTL) data.
- Differential gene expression analysis using the Gene Expression Omnibus (GEO) dataset GSE63359.
- Mendelian randomization (MR) and colocalization analyses to establish causal links.
- Validation using RT-qPCR and enzyme-linked immunosorbent assay (ELISA) on clinical KOA and control samples.
Main Results:
- Extracellular matrix protein 1 (ECM1) was identified as a protein causally associated with KOA risk.
- Colocalization analysis supported ECM1 as a potential therapeutic target for KOA.
- Clinical validation revealed significantly higher ECM1 levels in KOA patients compared to controls.
- ECM1 demonstrated strong diagnostic efficacy for KOA with an area under the curve (AUC) of 0.85.
Conclusions:
- ECM1 is implicated as a risk factor in the pathogenesis of knee osteoarthritis.
- ECM1 represents a promising diagnostic biomarker and potential therapeutic target for KOA.
- This study provides a foundation for developing targeted interventions for KOA.
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