Abstract Background Gout risk assessment is currently reactive, relying on hyperuricaemia. However, a significant clinical gap exists for individuals who develop gout despite maintaining “normal” 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. Methods We analyzed large-scale plasma proteomic data (2,920 proteins) from 33,147 normouricaemic individuals (baseline serum urate < 360 μmol/L) in the UK Biobank. To ensure findings were not artifacts of specific algorithms, we employed a “robustness-first” machine-learning framework encompassing 756 model configurations. Longitudinal protein trajectories were traced up to 15 years prior to diagnosis. Incident osteoarthritis was used as a negative control to evaluate specificity. Results A 10-protein signature (including VSIG4, UBQLN3, and MB) predicted incident gout with high discrimination (ROC-AUC = 0.892). 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 10–15 years before clinical diagnosis, even while serum urate remained within the normal range. The signature showed minimal discrimination for osteoarthritis (AUC ≈ 0.60). Conclusions 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.
Yuan et al. (Wed,) studied this question.