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

BACKGROUND: CYP2C19 metabolises many medications. Its enzymatic activity can be inferred from genetic variants within CYP2C19 that link 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 reveal interacting genes and pathways that underlie CYP2C19 effects on drug response and health consequences. A discovery methylome-wide association study (MWAS) was conducted in the Generation Scotland (n = 18,396) to investigate the non-linear and linear effects of CYP2C19 metaboliser status on DNA methylation. A targeted replication analysis on significant CpG sites from the discovery MWAS was conducted in Lothian Birth Cohorts of 1921 and 1936 (n = 1238). Pathway enrichment analysis was conducted for significant cytosine-guanine dinucleotide (CpG) sites. We examined whether the associations between CYP2C19 metaboliser status and DNA methylation were independent of the use of drugs that are inducers, inhibitors, or substrates of the CYP2C19 enzyme through interaction analysis. RESULTS: <0.05). Nineteen CpG sites, annotated to genes involving drug metabolism, inflammation, lipid levels, and Type 2 diabetes, demonstrated non-linear associations with CYP2C19 metaboliser status. Among the significant CpG sites in the discovery sample, there was a high correlation of standardised regression coefficients between the discovery and replication samples (r = 0.92). We found enrichment in biological processes involving metabolic activities and the Cytochrome P450 pathway. CYP2C19 metaboliser status did not interact with CYP2C19-related medication use to affect methylation of non-linear CpG signals. CONCLUSIONS: 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.