Pos0155 Pre-Diagnostic Immunomodulatory Amino Acid Metabolites and Risk of Gout, Accounting for Serum Urate: A Prospective Study of 249,677 Individuals and Mendelian Randomization Analyses

Background: Gout, the most common form of inflammatory arthritis (affecting 5.2% of US adults), is a metabolic condition influenced by genetics as well as environmental factors. Small-scale, cross-sectional studies of Asian men with preexisting gout implicated certain amino acids, but their generalizability beyond Asian countries or in women is unclear. Objectives: To prospectively investigate the pre-diagnostic, population-based metabolome for risk of hospitalized gout (i.e., accurate, severe, and costly cases; PPV 100% for gout1), accounting for baseline serum urate levels. Methods: We conducted pre-diagnostic metabolome-wide analysis among 249,677 UK Biobank participants (45% male, mean age 57.2 years at baseline) with NMR metabolomic profiling (N=168 metabolites, including eight amino acids) from baseline blood samples (2006-2010), without history of gout. We calculated multivariable hazard ratios (HRs) for incident hospitalized gout, before and after adjusting for serum urate levels; we included non-hospitalized incident gout cases in a sensitivity analysis. Potential causal effects were evaluated with two-sample Mendelian randomization using genetic association data from the GlobalGout consortium (N=100,661 cases and 2,106,003 controls). Results: Correcting for multiple testing, over a mean follow-up of 13.4 years, 107 metabolites were associated with incidence of hospitalized gout (N=2735 cases) before urate adjustment (Figure 1), 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), the branched chain amino acids isoleucine, leucine, and valine (inversely), and the inflammatory biomarker glycoprotein acetyls (GlycA; HR=2.48 2.15, 2.87, P=1.96x10-34) (Table 1). The associations for glycine, glutamine, and GlycA remained significant and directionally-consistent following urate adjustment (HR=0.83 95% CI: 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-hospitalized incident gout cases. Mendelian randomization corroborated the potential causal role of these amino acids 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. MR-Egger intercepts suggested no directional pleiotropy. Conclusion: These findings are consistent with glutamine and glycine's documented immune modulatory properties, including inhibition of activation of the NLRP3 inflammasome, a key component in the pathogenesis of gout flares, and experimental evidence suggesting glutamine levels are lower in synovial fluid samples taken during gout flares. From a clinical standpoint, these prospective findings with causal implications suggest a potential role for glycine and glutamine supplementation in lowering gout risk, as supported by trials where glycine or glutamine supplementation decreased insulin resistance2 and the inflammatory response,3 and increased urinary uric acid excretion.4 REFERENCES: 1 Singh. Arthritis Res Ther 2013. 2 Alves et al. Nutrients 2019. 3 Ortiz de Urbina et al. Int J Med Sci 2017. 4 Oshima et al. Nutrients 2019. Acknowledgements: NIL. Disclosure of Interests: Natalie McCormick: None declared, Amit Joshi Regeneron Pharmaceuticals, Regeneron Pharmaceuticals, Chio Yokose: None declared, Bing Yu: None declared, Adrienne Tin: None declared, Robert Terkeltaub Recently served or currently serves as a consultant for Allena, LG Chem, Fortress/Urica, Selecta Biosciences, Horizon Therapeutics, Atom Bioscience, Acquist Therapeutics, Generate, Biomedicines, Astra-Zeneca, and Synlogic., Astra-Zeneca (previous), Tony Merriman: None declared, Oana Zeleznik: None declared, A. Heather Eliassen: None declared, Gary Curhan Chief Medical Officer at OM1, Inc, GSK, Hang Korng Ea: None declared, Matthew Nayor: None declared, Laura Raffield: None declared, Hyon Choi Ani, LG, Horizon, Shanton, Protalix, Horizon.