循环尿酸盐的性别特异性表观遗传特征及其在卡介苗接种后的增加。

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

作者信息

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

机构信息

Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany.

TWINCORE, a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany.

出版信息

Res Sq. 2024 Jul 22:rs.3.rs-4498597. doi: 10.21203/rs.3.rs-4498597/v1.

DOI:10.21203/rs.3.rs-4498597/v1

PMID:39108482

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11302698/

Abstract

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.

摘要

背景

尿酸浓度及尿酸稳态的生理调节存在明显的性别差异。DNA甲基化已被证明可解释相当一部分血清尿酸的变异，介导基因对尿酸浓度的影响，并与心脏代谢特征共同调节。然而，尿酸浓度是否以性别依赖的方式与DNA甲基化相关尚不清楚。此外，值得研究的是，诸如接种疫苗等扰动后尿酸的变化是否以性别特异性方式与DNA甲基化相关。

方法

我们在一个由325名健康个体组成的荷兰队列中研究了DNA甲基化与血清尿酸浓度之间的关联。在卡介苗（BCG）接种前后测量尿酸浓度和DNA甲基化，卡介苗接种用作与痛风发作增加相关的一种扰动。关联分析包括联合分析、交互分析和按性别分层分析。使用三个独立队列对所识别的CpG位点进行验证。

结果

215个CpG位点与男性血清尿酸相关，而5个CpG位点与女性血清尿酸相关，表明存在性别特异性关联。卡介苗接种后循环尿酸浓度显著升高，且基线DNA甲基化以性别特异性方式与接种前后尿酸浓度的差异相关。与男性尿酸浓度相关的CpG位点在神经保护途径中富集，而在女性中，与尿酸变化相关的CpG位点与脂质和葡萄糖代谢有关。