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

Natalie McCormick; Amit D Joshi; Chio Yokose; Bing Yu; Adrienne Tin; Robert Terkeltaub; Tony R Merriman; Oana Zeleznik; A Heather Eliassen; Gary C Curhan; Hang-Korng Ea; Matthew Nayor; Laura M Raffield; Hyon K Choi

doi:10.1002/acr.25420

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

Arthritis Care Res (Hoboken). 2024 Aug 21. doi: 10.1002/acr.25420. Online ahead of print.

Authors

Affiliations

¹ Massachusetts General Hospital and Harvard Medical School, Boston, and Arthritis Research Canada, Vancouver, British Columbia, Canada.
² Brigham and Women's Hospital, Boston, Massachusetts.
³ Massachusetts General Hospital and Harvard Medical School, Boston.
⁴ The University of Texas Health Science Center at Houston.
⁵ University of Mississippi Medical Center, Jackson.
⁶ University of California San Diego, La Jolla.
⁷ University of Alabama at Birmingham and the University of Otago, Dunedin, New Zealand.
⁸ Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
⁹ Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
¹⁰ Université Paris Cité, Paris, France.
¹¹ Boston University, Massachusetts.
¹² University of North Carolina at Chapel Hill.

PMID: 39169570
DOI: 10.1002/acr.25420

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.

Abstract

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