First Pharmacoepigenomics in Personalized Medicine: CpG-PGx SNPs as New Candidates for a Systematic Insight into Genomic-Epigenomic-Phenomic-Pharmacogenomics (G-E-Ph-PGx) Axis

Background: There are important gaps in describing the associations between variants found by GWAS and various phenotypes. Prior reports suggested that SNPs in regulatory regions should be more investigated to uncover these associations. Thus, this study initiated a novel method along with Pharmacoepigenomics suggesting a new coined term “CpG-PGx SNP”. Methods: The rationale behind our analysis strategy was based on the impact of SNPs playing dual roles both in the CpG site disruption/formation and having PGx associations. Thus, we employed GeneCards (relevance score), PharmGKB (significant p-value), and GWAS catalog data for each gene (p<E-8). Following obtaining the 25 best-scored genes of four major epigenetic processes (methylation, demethylation, acetylation, and deacetylation), we generated two lists of candidate genes including potential CpG-PGx SNPs 2 of 22 and possible CpG-PGx SNPs. Results: Among 2,900 significant PGx annotations, we found 99 potential CpG-PGx SNPs related to 16 genes. CYP2B6, CYP2C19, CYP2D6, and COMT genes were the top genes. Additionally, we found 1,230 significant GWAS-based SNPs, among them 329 CpG-SNPs related to 48 genes with at least one CpG site disruption/formation. The top gene with the highest CpG-SNPs was TET2, followed by JMJD1C, and HDAC9. Importantly, we detected some synonymous variants in Epigenetically Modifiable Accessible Region (EMAR) which can open new insights into undiscovered roles of these SNPs. We identified 173 CpG-Disruptive SNPs, 155 CpG-Forming SNPs, and just 1 CpG SNP with both impacts. Conclusion: In conclusion, here we introduced CpG-PGx SNP for the first time, suggested 3 major genes playing crucial roles in Pharmacoepigenomics (PEpGx), CYP2D6 as the heart of PEpGx, and TET2 with the highest possibility of having CPG-PGx SNPs. We believe that his novel technological advance potentially will help the scientific community to utilize “CpG-PGx SNP” to unravel complex disease driven genetic and epigenetic interactions yielding therapeutic opportunities.