Acyl-Alkyl-Phosphatidylcholine C40:6 is Potentially a Causal Biomarker for Obesity-Related Knee Osteoarthritis: Data from 4 Independent Cohorts

Objectives To identify potential causal biomarkers for obesity-related knee osteoarthritis (OB+OA+) by metabolome-wide association analysis (MWA) and Mendelian randomization (MR). Methods Four cohorts were included: the Newfoundland Osteoarthritis Study (NFOAS) as discovery, the Tasmanian Older Adult Cohort Study (TASOAC) and Longitudinal Evaluation in the Arthritis Program: Osteoarthritis Study (LEAP OA) as replications, and the Multicenter Osteoarthritis Study (MOST) for assessing longitudinal prediction. OB+OA+ was defined as either end-stage or radiographic knee OA with BMI≥30 kg/m 2 . Plasma metabolomic profiling and genome-wide genotyping were performed. Regression models were used to identify biomarkers for OB+OA+ and MR for assessing causal relationships. Results Metabolome-wide association analysis of 310 OB+OA+ and 99 OB-OA+ patients from the NFOAS identified that acyl-alkyl-phosphatidylcholine C40:6 (PC ae C40:6) was associated with OB+OA+ at metabolome-wide significance (P=1.80×10^-6), which was replicated in the TASOAC including 102 OB+OA+ and 254 OB-OA+ and the LEAP OA including 118 OB+OA+ and 114 OB-OA+ (P≤7.78×10^-3) (Figure 1A). MR analyses showed causal relationships of PC ae C40:6 with knee OA and obesity (Figure 1B). Our longitudinal data showed that the baseline PC ae C40:6 predicted overweight status and BMI at 10-year follow-up in the TASOAC (n=159; P<0.02) and incidence radiographic and symptomatic knee OA at 5-year follow-up in the MOST (n=337; P<0.03) in subjects with baseline normal weight (Figure 1C,D). Furthermore, structural equation modeling analysis in the NFOAS (n=526) revealed that PC ae C40:6 had a significant indirect via obesity and a direct effect on knee OA (all P<0.001). Conclusion Our data suggested a causal relationship between PC ae C40:6 and OB+OA+. PC ae C40:6 could be a promising biomarker for monitoring OB+OA+ disease progression and a novel target for developing new therapies.