The non-linear and linear effects of CYP2C19 metaboliser status on DNA methylation: a methylome-wide association study
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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
Forty-eight CpG sites were significantly associated with the quadratic term of CYP2C19 metaboliser status (PBonferroni<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.
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
Forty-eight CpG sites were significantly associated with the quadratic term of CYP2C19 metaboliser status (PBonferroni<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.
Date Issued
2026-06-10
Date Acceptance
2026-03-30
Citation
Clinical Epigenetics, 2026, 18
ISSN
1868-7075
Publisher
BMC
Journal / Book Title
Clinical Epigenetics
Volume
18
Copyright Statement
© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Publication Status
Published
Article Number
111
Date Publish Online
2026-04-22