Abstract
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 the⍰use 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 status⍰did 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.
Competing Interest Statement
AMM previously received support from The Sackler Trust, Illumina and speaker fees from Illumina and Janssen. The remaining authors declare that they have no competing interests.
Footnotes
We have removed the PheWAS in this MWAS and will formulate PheWAS in a separate study. We have also additionally investigated the non-linear effects of CYP2C19 metaboliser status on DNA methylation to deepen the understanding of the relationship between CYP2C19 enzymatic activity and health implications with drug use, where current evidence is limited. We have also included a more comprehensive list of drugs that are associated with the CYP2C19 gene. We have also specified their relationship with the CYP2C19 enzyme (inducer, inhibitor, and substrate) when examining the interaction effect between CYP2C19 metaboliser status and CYP2C19-metabolised medications use on DNA methylation.