The linear and non-linear effects of CYP2C19 metaboliser status on DNA methylation: a methylome-wide association study

CYP2C19 metabolises many medications e.g., antidepressants, proton pump inhibitors and its enzymatic activity can be inferred from genetic variants within its encoding gene, linking to the efficacy of drug treatments and their side effects. It is however unclear if enzymatic activity is associated with local or widespread differences in DNA methylation. DNA methylation differences associated with CYP2C19 metabolising status may also have the potential to reveal interacting genes and pathways that underly CYP2C19 effects on drug response and health consequences. A methylome-wide association study was conducted in the Generation Scotland cohort (n=18,396) to investigate the linear and non-linear effects of CYP2C19 metaboliser status on genome-wide DNA methylation. Pathway enrichment analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with CYP2C19 metaboliser status. We examined whether the associations between CYP2C19 metaboliser status and DNA methylation were independent of theuse of drugs that are inducers, inhibitors, or substrates of the CYP2C19 enzyme by interaction analysis. Forty-eight CpG probes were significantly associated with both linear and quadratic terms of CYP2C19 metaboliser status (PBonferroni < 0.05). These CpG are annotated to genes involving drug metabolism, inflammation, lipid level, and Type 2 diabetes. Pathway enrichment analysis showed enrichment in biological processes involving metabolic activities and the Cytochrome P450 pathway. However, DNA methylation signals associated with CYP2C19 metaboliser statusdid not vary by CYP2C19-related medication use. This research suggests that genetically-determined CYP2C19 metaboliser status is associated with both local and distal DNA methylation. These associations are independent of whether individuals were receiving drugs that are related to this enzyme.