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Background <p>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.</p> Methods <p>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 <i>Bacillus Calmette-Guérin</i> (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Zhaoli Liu,
  • Tania O. Crișan,
  • Cancan Qi,
  • Manoj Kumar Gupta,
  • Xuan Liu,
  • Simone J. C. F. M. Moorlag,
  • Valerie A. C. M. Koeken,
  • Xun Jiang,
  • Mohamad Ballan,
  • 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

摘要

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 Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis.

Results

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.

Conclusions

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.