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Author(s): Xiaowen Huang [sup.1] , Qinglin Zhao [sup.1] , Dankang Li [sup.1] , Bingnan Ren [sup.1] , Limin Yue [sup.1] , Fengxian Shi [sup.1] , Xiliang Wang [sup.1] , Caifang [...], 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.sup.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.

Author(s): Dankang Li [sup.1], Qinglin Zhao [sup.1], Xiaowen Huang [sup.1], Chengda Zhang [sup.2], Opolot Godfrey [sup.1], Weidong Zhang [sup.1] Author Affiliations: (1) Department of Epidemiology, School of Public Health, Zhengzhou [...], Background 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. Methods 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. Results 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. Conclusions 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.