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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\u2010sample Mendelian randomization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u20130.75,\n                      <jats:italic>P<\/jats:italic>\n                      = 8.3 \u00d7 10\n                      <jats:sup>\u22128<\/jats:sup>\n                      ; glycine HR 0.69, 95% CI 0.61\u20130.78,\n                      <jats:italic>P<\/jats:italic>\n                      = 3.3 \u00d7 10\n                      <jats:sup>\u22129<\/jats:sup>\n                      between extreme quintiles), and glycoprotein acetyls (HR 2.48, 95% CI 2.15\u20132.87,\n                      <jats:italic>P<\/jats:italic>\n                      = 1.96 \u00d7 10\n                      <jats:sup>\u221234<\/jats:sup>\n                      ). Associations remained significant and directionally consistent following urate adjustment (HR 0.83, 95% CI 0.70\u20130.98; HR 0.86, 95% CI 0.76\u20130.98; HR 1.41, 95% CI 1.21\u20131.63 between extreme quintiles), respectively; corresponding HRs per SD were 0.91 (95% CI 0.86\u20130.97), 0.94 (95% CI 0.91\u20130.98), and 1.10 (95% CI 1.06\u20131.14). 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 \u22120.05 mg\/dL (95% CI \u22120.08 to \u22120.01) and \u22120.12 mg\/dL (95% CI \u22120.22 to \u22120.03) per SD of glycine and glutamine, respectively, and odds ratios of 0.94 (95% CI 0.88\u20131.00) and 0.81 (95% CI 0.67\u20130.97) for gout.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These prospective findings with causal implications could lead to biomarker\u2010based risk prediction and potential supplementation\u2010based interventions with glycine or glutamine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acr.25420","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:53:46Z","timestamp":1724288026000},"page":"1666-1674","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Prediagnostic Amino Acid Metabolites and Risk of Gout, Accounting for Serum Urate: Prospective Cohort Study and Mendelian Randomization"],"prefix":"10.1002","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-8348","authenticated-orcid":false,"given":"Natalie","family":"McCormick","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Boston, and Arthritis Research Canada  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit D.","family":"Joshi","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7557-3303","authenticated-orcid":false,"given":"Chio","family":"Yokose","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School  Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Yu","sequence":"additional","affiliation":[{"name":"The University of Texas Health Science Center at Houston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4207-5866","authenticated-orcid":false,"given":"Adrienne","family":"Tin","sequence":"additional","affiliation":[{"name":"University of Mississippi Medical Center  Jackson"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Terkeltaub","sequence":"additional","affiliation":[{"name":"University of California San Diego  La Jolla"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0844-8726","authenticated-orcid":false,"given":"Tony R.","family":"Merriman","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham and the University of Otago  Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oana","family":"Zeleznik","sequence":"additional","affiliation":[{"name":"Harvard Medical School and Brigham and Women's Hospital  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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Chan School of Public Health  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary C.","family":"Curhan","sequence":"additional","affiliation":[{"name":"Harvard Medical School and Brigham and Women's Hospital  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang\u2010Korng","family":"Ea","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Nayor","sequence":"additional","affiliation":[{"name":"Boston University  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Raffield","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyon K.","family":"Choi","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard 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