Association of methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) genes promoter methylation pattern with the risk of essential hypertension

Methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) are key enzymes in the metabolism of homocysteine pathway whose dysfunction can lead to essential hypertension (EH). This study aimed to investigate the possible association of MTHFR and CBS genes promoter methylation patterns with the risk of EH. We also aimed to search differentially expressed microRNAs (miRs) and demonstrate the role of miRs in the aberrant DNA methylation in essential hypertensive patients by targeting DNA methyltransferases (DNMTs).

20 essential hypertensive patients and 20 healthy controls were selected. DNA methylation levels of 10 CpG dinucleotides on MTHFR and 19 CpG dinucleotides on CBS genes promoter was measured using Bisulfite-Sequencing PCR (BSP). The GSE118578 profile was downloaded from the GEO database to identify differentially expressed miRs in hypertensive patients and R statistical software was used to analyze the data. Enrichment analysis was conducted to predict target genes using databases of Targetscan, and miRDB-MicroRNA Target Prediction Database.

No significant association between MTHFR gene methylation and EH was observed. There was a significant association between one of the CpG sites of CBS gene promoter (CpG19 (+1035C)) and EH [OR = 5.3(0.895–31.393), p = 0.047]. Furthermore, we reported a list of miRs that may have an essential role in regulating DNA methylation by targeting DNMTs.

Our findings showed that hypermethylation of CpG19 (+1035C) of CBS gene promoter could increase the risk of EH. Methylation status of MTHFR gene had no significant association with EH. Also, in-silico investigation showed that miRs may affect aberrant genes methylation through altering DNMTs biogenesis.