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

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.