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

Abstract

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.