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

Objective Our objective was to prospectively investigate prediagnostic population‐based metabolome for risk of hospitalized gout (ie, most accurate, severe, and costly cases), accounting for serum urate. Methods We conducted prediagnostic metabolome‐wide analyses among 249,677 UK Biobank participants with nuclear magnetic resonance 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 hospitalized incident gout, before and after adjusting for serum urate levels; we included patients with nonhospitalized incident gout 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 = 2,735) before urate adjustment, including glycine and glutamine (glutamine HR 0.64, 95% confidence interval CI 0.54–0.75, P = 8.3 × 10 −8 ; glycine HR 0.69, 95% CI 0.61–0.78, P = 3.3 × 10 −9 between extreme quintiles), and glycoprotein acetyls (HR 2.48, 95% CI 2.15–2.87, P = 1.96 × 10 −34 ). Associations remained significant and directionally consistent following urate adjustment (HR 0.83, 95% CI 0.70–0.98; HR 0.86, 95% CI 0.76–0.98; HR 1.41, 95% CI 1.21–1.63 between extreme quintiles), respectively; corresponding HRs per SD were 0.91 (95% CI 0.86–0.97), 0.94 (95% CI 0.91–0.98), and 1.10 (95% CI 1.06–1.14). Findings persisted when including patients with nonhospitalized incident gout. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of −0.05 mg/dL (95% CI −0.08 to −0.01) and −0.12 mg/dL (95% CI −0.22 to −0.03) per SD of glycine and glutamine, respectively, and odds ratios of 0.94 (95% CI 0.88–1.00) and 0.81 (95% CI 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.