Work

DNA methylation reveals molecular heterogeneity and urate excretion-associated subtypes of gout

Year: 2026

Type: preprint

Abstract: ABSTRACT Background The molecular heterogeneity among gout patients remains largely unexplored, hindered the precise treatment for gout. Common indices for gout subtyping are cumbersome to measure, resulting in poor patient compliance. Methods We elucidated the molecular heterogeneity of gout and developed a simple, reliable classification method for gout subtypes based on genome-wide DNA methylation, to facilitate individualized treatment. Genome-wide DNA methylation profiling was conducted in two independent cohorts, comprising a discovery cohort (n = 108) and a validation cohort (n = 100) representing four clinical gout subtypes. Results We identified two gout subgroups associated with the fractional excretion of uric acid (FE UA ) but not with 24-hour urinary uric acid levels (UUE) based on unsupervised clustering of whole-genome DNA methylation profiles, highlighting the contribution of epigenetic regulation to molecular heterogeneity in urate metabolism. Enrichment analysis links FE UA -associated subtypes to renal cell types, calcium related pathways and extended to the circulating immune compartment, with neutrophil- versus memory B cell-skewed leukocyte composition. A methylation-based classification model using 18 LASSO-selected CpGs with an XGBoost classifier effectively distinguished patients with high and low uric acid excretion, achieving excellent predictive performance (training cohort: AUC = 0.96, AP = 0.91; validation cohort: AUC = 0.86, AP = 0.85), outperforming the published model with clinical characteristics and SNPs. The signature site-associated genes NEK1 and TRPS1 display significant expression differences among urate-stratified patients and immune cells groups. TRPS1 may affect the AP-1/NF-κB inflammatory programme. Conclusions These findings reveal distinct DNA methylation signatures underlying gout heterogeneity and demonstrate the feasibility of DNA methylation markers for gout subtype classification. The proposed methylation-based model provides a promising approach for personalized management of gout.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.19.760079