Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China.
Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, 70112, USA.
Eur J Clin Nutr. 2020 Dec;74(12):1677-1684. doi: 10.1038/s41430-020-0657-9. Epub 2020 May 13.
Age and lower folate concentrations are well-known risk factors for cardiovascular disease (CVD), but the potential roles of age and folate deficiency in hyperhomocysteinemia (HHcy), especially in HHcy patients with abnormal methylation levels of key enzyme genes promoter in homocysteinemia (Hcy) pathway, have not been thoroughly evaluated. The purpose of this study was to evaluate the relationship between the promoter methylation levels of six key enzyme genes and age and serum folate level to better understand the pathogenesis of HHcy.
In 299 HHcy patients, six key enzyme genes promoter methylation was analyzed by PCR amplification and MethylTarget methods.
The betaine homocysteine methyltransferase (BHMT), Cystathionine β-synthase (CBS), and Methionine synthasegene (MTR) promoter methylation levels were positively associated with age and a negative correlation was found between CBS promoter methylation level and folate levels. However, these associations were not significant after Bonferroni correction. The stratified analysis showed that the methylation level of CBS gene promoter was positively correlated with age in males, and a positive correlation was also found between BHMT gene promoter methylation level and age in HHcy patients with a history of diabetes or hypertension. Moreover, stratified analysis according to sex revealed that the methylation levels of three CpG regions of BHMT_2, CBS_2, and CBS_3 were positively correlated with age in males after Bonferroni correction.
Our data suggested that age and folate deficiency may increase the risk of HHcy by mediating methylation of the promoter regions of key enzyme genes in the one-carbon metabolism pathway.
年龄和较低的叶酸浓度是众所周知的心血管疾病（CVD）危险因素，但年龄和叶酸缺乏在高同型半胱氨酸血症（HHcy）中的潜在作用，特别是在同型半胱氨酸代谢途径中关键酶基因启动子甲基化水平异常的 HHcy 患者中，尚未得到彻底评估。本研究旨在评估六个关键酶基因启动子甲基化水平与年龄和血清叶酸水平之间的关系，以更好地了解 HHcy 的发病机制。
在 299 例 HHcy 患者中，采用 PCR 扩增和 MethylTarget 方法分析了六个关键酶基因启动子的甲基化。
甜菜碱同型半胱氨酸甲基转移酶（BHMT）、胱硫醚-β-合酶（CBS）和蛋氨酸合成酶基因（MTR）启动子的甲基化水平与年龄呈正相关，CBS 启动子甲基化水平与叶酸水平呈负相关。然而，经 Bonferroni 校正后，这些相关性不显著。分层分析显示，CBS 基因启动子的甲基化水平与男性的年龄呈正相关，在有糖尿病或高血压病史的 HHcy 患者中，BHMT 基因启动子的甲基化水平与年龄也呈正相关。此外，根据性别进行分层分析表明，在男性中，BHMT_2、CBS_2 和 CBS_3 的三个 CpG 区域的甲基化水平与年龄呈正相关，经 Bonferroni 校正后。
我们的数据表明，年龄和叶酸缺乏可能通过调节一碳代谢途径中关键酶基因启动子区域的甲基化来增加 HHcy 的风险。
