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However, a significant clinical gap exists for individuals who develop gout despite maintaining \u201cnormal\u201d serum urate levels. We aimed to identify a plasma proteomic signature that defines a susceptibility state for gout years before clinical onset, specifically within individuals who are normouricaemic at baseline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed large-scale plasma proteomic data (2,920 proteins) from 33,147 normouricaemic individuals (baseline serum urate\u2009&lt;\u2009360\u2009\u03bcmol\/L) in the UK Biobank. To ensure findings were not artifacts of specific algorithms, we employed a \u201crobustness-first\u201d machine-learning framework encompassing 756 model configurations. Longitudinal protein trajectories were traced up to 15\u2009years prior to diagnosis. Incident osteoarthritis was used as a negative control to evaluate specificity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A 10-protein signature (including VSIG4, UBQLN3, and MB) predicted incident gout with high discrimination (ROC-AUC\u2009=\u20090.892). This signature identified a high-risk subgroup with a 4.46-fold increased hazard, independent of baseline serum urate and conventional risk factors. Notably, protein trajectories diverged between future cases and controls 10\u201315\u2009years before clinical diagnosis, even while serum urate remained within the normal range. The signature showed minimal discrimination for osteoarthritis (AUC\u2009\u2248\u20090.60).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In 33,147 normouricaemic individuals, plasma proteomics identifies a stable preclinical susceptibility state for gout that exists beyond the traditional serum urate paradigm. This 10-protein signature enables early risk stratification and offers a significant window for precision prevention a decade before clinical onset.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08505-3","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:55:25Z","timestamp":1782273325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of a 10-protein plasma signature for preclinical gout risk beyond serum urate: a robustness-first proteomic study in 33,147 normouricaemic individuals"],"prefix":"10.1186","volume":"24","author":[{"given":"Yue","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengping","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheshan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7601-376X","authenticated-orcid":false,"given":"Zhaoxiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"issue":"7","key":"8505_CR1","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1038\/s41584-020-0441-1","volume":"16","author":"M Dehlin","year":"2020","unstructured":"Dehlin M, Jacobsson L, Roddy E. 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