Identifying DNA methylation sites affecting drug response using electronic health record-derived GWAS summary...

Area of Science:

• Pharmacogenomics
• Epigenetics
• Drug Response

Background:

• Adverse drug responses (ADRs) cause significant mortality, with genetics playing a partial role.
• Epigenetic mechanisms, like DNA methylation (DNAm), are increasingly recognized as contributors to ADR variability.
• Personalizing drug regimens requires understanding the impact of DNAm on drug response.

Purpose of the Study:

• To identify DNA methylation sites associated with drug response phenotypes for anticoagulant and cardiometabolic medications.
• To leverage large-scale genetic and epigenetic data for robust identification of DNAm impacts on drug response.
• To improve the prediction and prevention of adverse drug responses through epigenetic insights.

Main Methods:

• Instrumental variable analysis was employed to integrate GWAS summary statistics from UK Biobank EHRs with mQTL data from the GoDMC.
• Utilized the largest publicly available pharmacogenomic GWAS for a robust sample size.
• Focused on identifying DNAm sites influencing responses to warfarin and statins.

Main Results:

• Identified 71 DNAm sites associated with warfarin response, including sites near VKORC1, CYP2C9, CYP2C19, and the HLA gene family.
• Identified 17 DNAm sites associated with statin response, with 8 near the APOB gene.
• No novel significant epigenetic associations were found for metformin response.

Conclusions:

• Specific DNA methylation sites are linked to individual responses to warfarin and statins.
• These findings highlight the potential of DNAm as a biomarker for predicting and mitigating adverse drug responses.
• Epigenetic insights can advance personalized medicine, particularly for cardiovascular and metabolic drug therapies.