Objectives Our objective was to prospectively investigate pre‐diagnostic population‐based metabolome for risk of hospitalized gout (i.e., most accurate, severe, and costly cases), accounting for serum urate. Methods We conducted pre‐diagnostic metabolome‐wide analyses among 249,677 UK Biobank participants with NMR metabolomic profiling (N=168 metabolites, including eight amino acids) from baseline blood samples (2006‐2010), without a history of gout. We calculated multivariable hazard ratios (HRs) for incident hospitalized gout, before and after adjusting for serum urate levels; we included non‐hospitalised incident gout cases in a sensitivity analysis. Potential causal effects were evaluated with two‐sample Mendelian randomization. Results Correcting for multiple testing, 107 metabolites were associated with incidence of hospitalized gout (N=2735) before urate adjustment, including glycine and glutamine (inversely; HR=0.64 [95% CI: 0.54, 0.75], P=8.3x10 ‐8 and HR=0.69 [0.61, 0.78], P=3.3x10 ‐9 between extreme quintiles, respectively), and glycoprotein acetyls (GlycA; HR=2.48 [2.15, 2.87], P=1.96x10 ‐34 ). Associations remained significant and directionally‐consistent following urate adjustment (HR=0.83 [0.70, 0.98], 0.86 [0.76, 0.98], 1.41 [1.21, 1.63] between extreme quintiles), respectively; corresponding HR per SD were 0.91 (0.86, 0.97), 0.94 (0.91, 0.98), and 1.10 (1.06, 1.14). Findings persisted when including non‐hospitalised incident gout cases. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of ‐0.05 mg/dL (‐0.08, ‐0.01), and ‐0.12 mg/dL (‐0.22, ‐0.03), per SD of glycine and glutamine, respectively, and ORs 0.94 (0.88, 1.00), and 0.81 (0.67, 0.97), for gout. Conclusion These prospective findings with causal implications could lead to biomarker‐based risk prediction and potential supplementation‐based interventions with glycine or glutamine.

Pre‐Diagnostic Amino Acid Metabolites and Risk of Gout, Accounting for Serum Urate: Prospective Cohort Study and Mendelian Randomization