Androgen receptor DNA methylation is an independent determinant of glucose metabolic disorders in women; testosterone plays a moderating effect
雄激素受体DNA甲基化是女性葡萄糖代谢紊乱的独立决定因素而睾酮起到调节作用
The Chinese Clinical Trial Registration. ChiCTR-OOC-15006699 (URL:http://www.chictr.org.cn/showproj.aspx?proj=11375).
Funding information: China Postdoctoral Science Foundation, Grant/Award Number: 2016M602264; Excellent Youth Development Foundation of Zhengzhou University, Grant/Award Number: 2018ZDGGJS052; Key Scientific and Technological Project Foundation of Henan Province, Grant/Award Number: 182102310562; National Key Research and Development Program of China, Grant/Award Numbers: 2016YFC0900803, 2019YFC1710002; National Natural Science Foundation of China, Grant/Award Numbers: 21607136, 21806146
Abstract
enBackground
We have previously shown that serum testosterone was associated with impaired fasting glucose (IFG) and type 2 diabetes (T2D). Testosterone can be acting through binding the androgen receptor (AR). Therefore, we aimed to explore the independent associations of AR DNA methylation (ARm) with IFG and T2D and the moderation effects of serum testosterone on the associations.
Methods
A case-control study with 1065 participants including 461 men and 604 women was performed. ARm in peripheral blood sample and serum testosterone were measured using pyrosequeuncing and liquid chromatography-tandem mass, respectively. Multivariable logistic regression was performed to estimate the associations of ARm (including 2 cytosine-phosphoguanine [CpG] islands and average methylation levels) with different glucose status. Serum testosterone was used as a moderator to estimate the moderation effect.
Results
After multivariate adjustment, CpG 1, 2 and CpG average methylation were all significantly associated with IFG (CpG 1: Odds ratio (OR) = 4.80, 95% confidence interval (CI): 2.24-10.27; CpG 2: OR = 4.35, 95% CI: 2.50-7.58; CpG average: OR = 11.73, 95% CI: 5.36-25.67) in women. In addition, testosterone played negative moderation effects in above associations. Moreover, no significant independent associations of methylation levels with T2D was observed both in men and women.
Conclusion
Our findings demonstrate that ARm was positively associated with IFG in women and the associations would be weakened by testosterone. The individuals experiencing low testosterone and ARm levels reported a lower state of IFG than those who experienced high levels of testosterone and ARm in women.
摘要
zh背景
我们之前的研究显示血清睾酮与空腹血糖受损(impaired fasting glucose，IFG)和2型糖尿病(type 2 diabetes, T2D)相关。睾酮可以通过与雄激素受体(androgen receptor, AR)结合发挥作用。因此，我们旨在探讨AR DNA甲基化与IFG和T2D的关系，以及血清睾酮对上述关联的调节作用。
方法
本研究采用病例对照研究设计，共纳入1065名研究对象，其中包括461名男性和604名女性。分别采用焦磷酸测序和液相色谱串联质谱法测定外周血样品中的AR DNA甲基化和血清睾酮水平。通过多变量logistic回归评估AR DNA甲基化(包括2个胞嘧啶-磷酸鸟嘌呤(cytosine-phosphoguanine, CpG)岛和平均甲基化水平)与不同葡萄糖状态的相关性。此外，血清睾酮被用作调节因子来评估其调节效应。
结果
经过多变量调整后，在女性中，CpG 1、2和CpG平均甲基化水平均与IFG显著相关(CpG 1: OR=4.80, 95% CI: 2.24-10.27；CpG 2: OR = 4.35, 95% CI: 2.50-7.58；CpG平均值: OR = 11.73, 95% CI: 5.36-25.67)。此外，睾酮在上述相关性中发挥了负向调节作用。另外，无论在男性还是女性中，均未观察到甲基化水平与T2D之间存在显著的关联。
结论
我们的研究结果表明，在女性中，AR DNA甲基化水平与IFG呈正相关，而这种相关性会被睾酮削弱。与那些睾酮水平和AR DNA甲基化水平较高的人相比，睾酮和AR DNA甲基化水平较低的人，其IFG患病概率较低。
