PII-079 - IDENTIFYING EPIGENTIC INFLUENCES ON DRUG METABOLISM: MULTI-OMIC ANALYSES IN AFRICAN AMERICAN HEPATOCYTES

K. Carver¹, C. Clark², Y. Zhong², G. Yang³, M. Mishra², C. Alarcon², M. Perera⁴; ¹Northwestern University, Chicago, IL, United States, ²Feinberg School of Medicine, Northwestern University, ³Feinberg School of Medicine, Northwestern University, , United States, ⁴Northwestern University.

Background: Precision medicine promises to improve patient outcomes by personalizing care to an individual’s specific genetic makeup. Because variability in gene expression contributes to differences in drug response, clarifying the roles of genetic and epigenetic variation in regulating gene expression, specifically in genes related to pharmacokinetics, is critical to advancing precision medicine. Though the effects of single nucleotide polymorphisms (SNPs) on gene expression are well studied, the role of DNA methylation is less clear. Because DNA methylation patterns differ between racial groups, epigenomic studies must be performed on diverse cohorts to account for population-specific effects.

Methods: Methylation quantitative trait loci (methQTL) analysis identifies SNPs associated with changes in DNA methylation levels at CpG sites across the genome. Similarly, expression quantitative trait methylation (eQTM) analysis identifies CpG sites associated with changes in gene expression. We performed methQTL and eQTM analyses on 78 hepatocyte samples derived from African American donors to identify SNPs associated with differential methylation and to identify methylation sites associated with gene expression in African Americans.

Results: 170,548 methQTLs were identified, affecting the methylation levels at 8,474 methylation sites. Additionally, 1048 eQTMs were found, affecting the expression of 352 genes. For 201 of these genes, the GTEX project did not identify any genetic variation affecting the expression of these genes in liver tissue. Of particular interest is the association of rs1332018, a 5’ UTR SNP, with methylation changes at 6 CpG sites (all in the promotor) affecting the expression of GSTM3, an enzyme that is involved in the detoxification of several drugs. This SNP has large differences in allele frequency and linkage disequilibrium between populations. We altered this SNP using prime editing and measured the effects on DNA methylation, gene expression, and GSTM3 activity.

Conclusion: This study’s use of African American samples demonstrates that multi-omic analysis in minority populations can identify factors (both genetic and epigenetic) that may affect the pharmacokinetics of currently used drugs. Many of these factors are population-specific and may explain differences in drug response between populations.