Changes in DNA methylation in APOE and ACKR3 genes in multiple sclerosis patients and the relationship with their heavy metal blood levels

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease with demyelinated lesions in the central nervous system caused by genetic and environmental factors. DNA methylation as an epigenetic change influenced by environmental factors, including heavy metals has been implemented in MS disease. We investigated the correlation of DNA methylation changes in APOE and ACKR3 genes in MS patients and the possible association with blood concentration of arsenic (As), cadmium (Cd) and lead (Pb) as major heavy metal pollutants. This study included 69 relapsing-remitting multiple sclerosis (RR-MS) patients and 69 age/gender-matched healthy subjects. The HRM real-time PCR method was used to investigate the changes in DNA methylation and heavy metal concentrations were measured by electrothermal atomic absorption spectrometry. Our results showed that the methylation pattern in the ACKR3 gene of the patient group was more hypomethylated, while in the case of the APOE gene, this pattern was more towards hypermethylation compared to healthy subjects. Moreover, the blood levels of As and Cd metals, but not Pb, were significantly higher in the patient group compare to the control group (p <= 0.05). The data indicate that the increase in expression of ACKR3 gene by hypomethylation and the decrease in expression of APOE gene via hypermethylation are possibly involved in the onset and progression of inflammatory processes in MS patients. The level of As can also lead to hypomethylation by disrupting the methylation patterns of the ACKR3 gene, resulting in increased expression in MS patients. Finally, we have shown that epigenetic changes can be an important factor in increasing and decreasing the expression of genes involved in the onset and/or progression of inflammatory processes in MS. Furthermore, exposure to heavy metals, especially As, by changing the natural patterns of DNA methylation can be effective in this disease.