Association between gene promoter methylation of the one-carbon metabolism pathway and serum folate among patients with hyperhomocysteinemia
Association between gene promoter methylation of the one-carbon metabolism pathway and serum folate among patients with hyperhomocysteinemia
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DOI：
10.1038/s41430-020-0657-9
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发表时间：
2020-05-13
影响因子：
4.7
通讯作者：
Zhang, Weidong
中科院分区：
文献类型：
--
作者：
Huang, Xiaowen;Zhao, Qinglin;Zhang, Weidong
目的年龄和叶酸水平降低是心血管疾病(CVD)的危险因素，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，尤其是同型半胱氨酸血症(Hcy)途径中关键酶基因启动子甲基化水平异常的HHcy患者，尚未得到深入研究。本研究旨在探讨6种关键酶基因启动子甲基化水平与年龄和血清叶酸水平的关系，以更好地了解HHcy的发病机制。方法对299例HHcy患者的6个关键酶基因启动子甲基化进行聚合酶链式反应和甲基化检测。结果甜菜碱同型半胱氨酸甲基转移酶(BHMT)、胱硫氨酸β合成酶(CBS)和蛋氨酸合成酶(MTR)基因启动子甲基化水平与年龄呈正相关，CBS基因启动子甲基化水平与叶酸水平呈负相关。然而，在Bonferroni校正后，这些关联并不显著。分层分析显示男性CBS基因启动子甲基化水平与年龄呈正相关，有糖尿病或高血压病史的HHcy患者BHMT基因启动子甲基化水平与年龄呈正相关。按性别分层分析显示，经Bonferroni校正后，男性BHMT_2、CBS_2和CBS_3三个CpG区域的甲基化水平与年龄呈正相关。结论年龄和叶酸缺乏可能通过介导单碳代谢途径关键酶基因启动子区甲基化而增加HHcy的风险。
Aim 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. Methods In 299 HHcy patients, six key enzyme genes promoter methylation was analyzed by PCR amplification and MethylTarget(TM) methods. Results The betaine homocysteine methyltransferase (BHMT), Cystathionine beta-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. Conclusions 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.