CBS gene polymorphism and promoter methylation‐mediating effects on the efficacy of folate therapy in patients with hyperhomocysteinemia

Abstract

Background A decrease in cystathionine beta‐synthase (CBS) enzyme activity could lead to hyperhomocysteinemia (HHcy). Studies have revealed that DNA methylation has a mediating effect on the development of diseases. The present study aimed to explore CBS promoter methylation‐mediating effects on the efficacy of folate treatment for HHcy. Methods HHcy patients were treated with folate (5 mg/day) for 90 days and then divided into a failure group (Hcy ≥ 15 μmol/l) and a success group (Hcy < 15 μmol/l) according to post‐treatment plasma Hcy levels. Genotyping of CBS gene (rs2851391 and rs706209) in patients (n = 638) was detected using a MassArray system (Sequenom, San Diego, CA, USA). The baseline DNA methylation levels of patients (n = 299) were detected using MethylTarget™ technology (Genesky Biotechnologies Inc., Shanghai, China). Results The CBS rs2851391 TC + CC genotype was related to a 57% reduction of failure risk in HHcy treatment compared to the TT genotype (95% confidence interval [CI] = 0.19–0.97). The CBS rs706209 CT + TT genotype had a 2.97‐fold increased risk of failure to treatment compared to the CC genotype (95% CI = 1.52–5.80). After adjustment for confounding factors, the odds ratio (95% CI) for the risk of failure in HHcy treatment in total and male patients was 0.55 (0.32–0.93) and 0.34 (0.16–0.69), respectively, for patients with higher methylation levels (≥ methylation median). Additionally, baseline CBS promoter methylation mediated 33.39% of the effect of rs2851391 on the efficacy of folate treatment for HHcy (ACME [average causal mediation effects]: –0.05, 95% CI = –0.11 to 0.00, p = 0.046). Conclusions The present study indicates that CBS gene polymorphism and promoter methylation could affect the efficacy of HHcy. There were potentially causal effects of genetic, epigenetic variations at the CBS rs2851391 locus on the efficacy of HHcy therapy with folate.

Emerging roles of cystathionine β-synthase in various forms of cancer

“…These conditions include cell growth and cell proliferation itself – at least in part due to the stimulatory effect of serum and/or various growth factors in the culture medium [ 18 ] and hypoxia – at least in part due to the action of hypoxia-inducible factor α and hypoxia-inducible factor β on the hypoxia-response element in the CBS promoter [ 19 ]. Importantly, CBS expression is also known to be regulated by the methylation status of CpG islands in its promoter [ [20] , [21] , [22] , [23] , [24] , [25] , [26] ]. Some of the mechanisms discussed above – alone or in combination – may contribute to the upregulation of CBS mRNA and CBS protein in various cancers (see below).…”

“…However, the expression of CBS in circulating tumor cells has not yet been investigated in clinical studies. A related approach may be the assessment of the CBS promoter's methylation status in circulating cell-free tumor DNA (cfDNA), in light of the fact the methylation of the CBS promoter regulates the expression of CBS [ [20] , [21] , [22] , [23] , [24] , [25] , [26] ]. However – as discussed earlier – the clinical data published so far are conflicting with respect to the role of hypo-vs hypermethylation of this promoter in various forms cancer [ 22 , 56 ].…”