Plasma Proteomics Identifies LEP and FABP4 as Key Mediators of Obesity-Related Knee Osteoarthritis

Objectives To identify and validate molecular markers for obesity-related knee osteoarthritis (OB + OA + ) by integrating proteomic and genetic data. Methods Plasma samples from 171 primary knee OA patients, including 86 OB+OA+ and 85 OB-OA+ patients, with age, sex, and comorbidities matched between the 2 groups, were analyzed using the Olink Explore HT platform, quantifying 5,416 proteins. Logistic regression models were utilized to identify significant proteins. Genetic variants located within the corresponding genes of the identified proteins were retrieved from the available genome-wide genotype data, and their associations with the identified protein expressions were examined. Results Proteomic analysis revealed leptin (LEP) and fatty acid-binding protein 4 (FABP4) as significantly associated with the OB+OA+ group (p < 9.23×10^-6) after adjusting for age, sex, hypertension, hyperlipidemia, other cardiovascular diseases, and diabetes, and controlling for multiple testing across 5,416 proteins (Figure 1A). Genetic analysis identified SNPs rs141614112 (G>A) in LEP (p < 0.04) and rs33998908 (delT) in FABP4 (p < 0.02) as variants associated with their respective protein concentrations (Figure 1B and C). However, neither variant demonstrated a significant association with OB+OA+ phenotype. Validation of the findings in 4 groups including OB+OA+, OB-OA+, OB+OA−, and OB-OA- with a large sample size is underway. Figure 1: (A) Volcano plot for proteome-wide association analysis results for obesity-related knee OA. Logistic regression modeling was used with adjustment for age, sex, BMI, and comorbidities. Dash line is proteome-wide significance for controlling multiple testing for 5,416 proteins. (B). Box plot for association between rs141614112 and LEP levels. (C). Box plot for association between rs33998908 and FABP4. Conclusion Our data demonstrated LEP and FABP4 as key protein biomarkers for OB+OA+. While genetic variants influenced circulating protein levels, their lack of direct association with the clinical phenotype suggests that environmental and metabolic factors may play a greater role in the manifestation of obesity-related knee OA.