Association between gene promoter methylation of the one-carbon metabolism pathway and serum folate among patients with hyperhomocysteinemia.

Abstract

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 MethylTargetTM 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.