Background: Previous studies reported that testosterone and DNA methylation of suppressor of cytokine signaling-3 (SOCS3) were associated with type 2 diabetes (T2D). Testosterone affects SOCS3 gene expression. Therefore, we aimed to investigate how the SOCS3 methylation mediates the relationship between testosterone and T2D among Chinese rural adults.
Methods: A case-control study comprised 365 T2D patients and 651 controls was conducted. Liquid chromatography-tandem mass spectrometry and MethylTarget were used to determine the levels of serum testosterone and DNA methylation of SOCS3 gene, respectively. The odds ratio (OR) of testosterone or SOCS3 methylation for T2D was calculated using logistic regression models, and β value of testosterone for SOCS3 methylation was evaluated by linear regression models. Furthermore, through mediation analysis the mediating effect of SOCS3 methylation on the association of testosterone with T2D was estimated.
Results: After adjusting for multiple variables, the protective effect of testosterone on T2D was found in men (OR = 0.61, 95% confidence interval [CI]: 0.47-0.80), and the methylation of Chr17:76356190 or Chr17:76356199 was negatively related to T2D in both men and women. Moreover, testosterone was positively associated with Chr17:76356190 methylation in men and Chr17:76356199 methylation in women (both P < .05). The mediation analysis showed that the Chr17:76356190 methylation partly mediated effect of testosterone on T2D in men was approximately 8.2%.
Conclusions: High levels of serum testosterone in men and Chr17:76356190 and Chr17:76356199 (SOCS3) methylation were related to a lower prevalent T2D. In addition, Chr17:76356190 methylation partially mediated the effect of testosterone on T2D in Chinese rural men.
背景: 既往研究表明血清睾酮水平和细胞因子信号传导抑制因子-3 (suppressor of cytokine signaling, SOCS)-3 的DNA甲基化水平与2型糖尿病(type 2 diabetes，T2D)有关。同时，睾酮影响SOCS3基因的表达水平。因此，本研究旨在在中国农村成年人中探讨SOCS3基因DNA甲基化对睾酮与T2D关联的中介作用。 方法: 本研究采用病例对照设计，共纳入365名T2D患者和651名正常人，采用液相色谱串联质谱法和MethylTarget法分别检测血清睾酮水平和SOCS3基因的DNA甲基化水平。运用logistic回归模型估计睾酮或SOCS3基因DNA甲基化对T2D的比值比(odds ratio, OR)，用线性回归模型评估睾酮水平对SOCS3基因DNA甲基化的β值。此外，我们通过中介分析探讨了SOCS3基因DNA甲基化对睾酮与T2D关联的中介作用。 结果: 校正多种混杂因素后，在男性中发现睾酮对T2D的保护作用(OR = 0.61, 95% 置信区间 (confidence interval, CI): 0.47-0.80)，在男性和女性中，Ch17:76356190或Ch17:76356199位点的DNA甲基化与T2D呈负相关。而且，睾酮与男性的Chr17:76356190位点的DNA甲基化和女性的Chr17:76356199位点的DNA甲基化呈正相关(P<0.05)。中介分析结果显示，在男性中，Ch17:76356190位点的DNA甲基化介导了8.2%的睾酮对T2D的影响。 结论: 男性高水平的血清睾酮和Chr17:76356190和Chr17:76356199 (SOCS3)位点DNA甲基化与较低的T2D流行有关。而且，在中国农村男性中，Ch17:76356190位点DNA甲基化部分介导了睾酮对T2D的影响。.
Keywords: 2型糖尿病; DNA methylation; DNA甲基化; mediation analysis; suppressor of cytokine signaling 3; testosterone; type 2 diabetes; 中介分析; 睾酮; 细胞因子信号传导抑制因子-3.
© 2021 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.