Skip to main content

Sex-specific epigenetic signatures of circulating urate and its increase after BCG vaccination.

Research square

Authors: Zhaoli Liu, Tania O Crișan, Cancan Qi, Manoj Kumar Gupta, Xuan Liu, Simone J C F M Moorlag, Valerie A C M Koeken, L Charlotte J de Bree, Vera P Mourits, Xu Gao, Andrea Baccarelli, Joel Schwartz, Frank Pessler, Carlos A Guzmán, Yang Li, Mihai G Netea, Leo A B Joosten, Cheng-Jian Xu

BACKGROUND: 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.

METHODS: 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 (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis. Validation of the identified CpG sites was conducted using three independent cohorts.

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

CONCLUSION: Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights have significant implications for the diagnosis, prevention, and treatment of various urate-related diseases and highlight the importance of personalized and sex-specific approaches in medicine.

PMID: 39108482

Participating cluster members