Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China.
Department of International Medicine, Beaumont Health System, Royal Oak, MI, 48073, USA.
Eur J Clin Nutr. 2020 Jul;74(7):1073-1083. doi: 10.1038/s41430-020-0611-x. Epub 2020 Mar 20.
Folate supplementation treatment is the first-line therapy in hyperhomocysteinaemia (HHcy). Up to 40% of HHcy patients do not benefit from folate therapy. Genetic and epigenetic factors of one-carbon metabolism (1-CM) might be identified as a predictor of folate supplementation treatment response. In the present study, we attempt to identify whether genetic and epigenetic factors might predict folate treatment response.
A total of 230 patients with HHcy were involved in this prospective cohort study. Differences between baseline concentrations and concentrations obtained at 90 days of treatment were calculated to evaluate the treatment response. General linear models and Pearson correlation was used to explore associations among single-nucleotide polymorphisms (SNPs), DNA methylation, and folate treatment response. Finally, mediation analysis was performed to investigate whether DNA methylation of MTRR mediates the association between SNPs and treatment response.
MTHFD rs1950902 and MTRR rs162036, rs1801394 was associated with the folate treatment response (P = 0.000, 0.048, and 0.043, respectively). CBS and CBS_2 DNA methylation was significantly associated with folate treatment response (P = 0.0009 and < 0.001). DNA methylation of MTHFR, MTR, and MTRR was also significantly associated with folate treatment response (P < 0.001). DNA methylation of MTRR and MTRR_1 mediated 40.71% and 40.47% of the effect of rs1801394 on folate treatment response, respectively.
Our results indicated that the 1-CM gene SNPs and DNA methylation was associated with folate treatment response and can be further evaluated relationship between SNPs and DNA methylation in 1-CM with treatment response in a larger sample.
叶酸补充治疗是高同型半胱氨酸血症（HHcy）的一线治疗方法。多达 40%的 HHcy 患者不能从叶酸治疗中获益。一碳代谢（1-CM）的遗传和表观遗传因素可能被确定为叶酸补充治疗反应的预测因子。在本研究中，我们试图确定遗传和表观遗传因素是否可以预测叶酸治疗反应。
本前瞻性队列研究共纳入 230 例 HHcy 患者。计算治疗前和治疗 90 天后的浓度差异，以评估治疗反应。采用广义线性模型和 Pearson 相关分析探讨单核苷酸多态性（SNP）、DNA 甲基化与叶酸治疗反应之间的关系。最后，进行中介分析以探讨 MTRR 的 DNA 甲基化是否介导 SNP 与治疗反应之间的关系。
MTHFD rs1950902 和 MTRR rs162036、rs1801394 与叶酸治疗反应相关（P=0.000、0.048 和 0.043）。CBS 和 CBS_2 的 DNA 甲基化与叶酸治疗反应显著相关（P=0.0009 和 <0.001）。MTHFR、MTR 和 MTRR 的 DNA 甲基化也与叶酸治疗反应显著相关（P<0.001）。MTRR 和 MTRR_1 的 DNA 甲基化分别介导了 rs1801394 对叶酸治疗反应影响的 40.71%和 40.47%。
我们的研究结果表明，1-CM 基因 SNP 和 DNA 甲基化与叶酸治疗反应相关，并且可以进一步评估更大样本中 SNP 和 1-CM 中 DNA 甲基化与治疗反应之间的关系。
