Sex-specific DNA methylation associations with circulating urate levels and BCG-induced urate changes

Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner.

We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis.

215 CpG sites are associated with serum urate in males, while 5 CpG sites are associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increase after BCG vaccination, and baseline DNA methylation is associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males are enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites are related to lipid and glucose metabolism.

Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights highlight the importance of personalized and sex-specific approaches in medicine.