Influence of Metabolic, Transporter, and Pathogenic Genes on Pharmacogenetics and DNA Methylation in Neurological Disorders

SIMPLE SUMMARY: The prevalence of neurodegenerative disorders has increased, yet reliable, pre-symptomatic biomarkers for early detection and subsequent preventive interventions remain elusive. The aim of our study was to understand the interplay between DNA methylation, a crucial biological process that modifies DNA activity, genetic composition, and the impact of drugs on neurodegenerative diseases. We distinguished two patient groups based on their DNA methylation levels and found unique drug-response patterns and gene-interaction dynamics within each group. These variations in gene interactions produced differential treatment responses that correlated with temporal changes in DNA methylation. Our findings highlight the critical role of specific genes, including CYP1A2, CYP2E1, CHAT, and various transporter genes, in shaping DNA methylation and treatment outcomes. Moreover, gene variants such as APOE and NBEA influenced disease progression and treatment response. The complexity of these interactions was further underscored by the varied responses of other genes such as the drug metabolizing genes CYP4F2, NAT2, and COMT. Our study highlights the potential of precision medicine in managing neurodegenerative disorders by tailoring treatments to individual genetic and epigenetic profiles. By deepening our understanding of these interactions, we can potentially improve treatment efficacy, thereby reducing the societal burden of neurodegenerative diseases. ABSTRACT: Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2, CYP2C9, CYP4F2, GSTP1, and NAT2, that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes (ABCB1, ABCC2, SLC2A9, SLC39A8, and SLCO1B1) and pathogenic genes (APOE, NBEA, and PTGS2). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders.