TY - JOUR T1 - Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor Binding Sites Influence AHR Ligand-Dependent Gene Expression JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.087312 SP - dmd.119.087312 AU - Drew R. Neavin AU - Jeong-Heon Lee AU - Duan Liu AU - Zhenqing Ye AU - Hu Li AU - Liewei Wang AU - Tamas Ordog AU - Richard M Weinshilboum Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/07/10/dmd.119.087312.abstract N2 - Greater than 90% of significant genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are in noncoding regions of the genome but only 25.6% are known expression quantitative trait loci (eQTLs). Therefore, the function of many significant GWAS SNPs remains unclear. We have identified a novel type of eQTL for which SNPs distant from ligand-activated transcription factor (TF) binding sites can alter target gene expression in a SNP genotype-by-ligand-dependent fashion that we refer to as "pharmacogenomic eQTLs" (PGx-eQTLs)--loci which may have important pharmacotherapeutic implications. In the present study, we integrated ChIP-seq with RNA-seq and SNP genotype data for a panel of lymphoblastoid cell lines (LCLs) to identify 10 novel cis PGx-eQTLs dependent on the ligand-activated TF aryl hydrocarbon receptor (AHR)--a critical environmental sensor for xenobiotic (drug) and immune response. Those 10 cis PGx-eQTLs were eQTLs only after AHR ligand treatment even though the SNPs did not create/destroy an AHR response element--the DNA sequence motif recognized and bound by AHR. Additional functional studies in multiple cell lines demonstrated that some cis PGx-eQTLs are functional in multiple cell types while others displayed SNP-by-ligand-dependent effects in just one cell type. Further, four of those cis PGx-eQTLs had previously been associated with clinical phenotypes, indicating that those loci might have the potential to inform clinical decisions. Therefore, SNPs across the genome that are distant from TF binding sites for ligand-activated TFs might function as PGx-eQTLs and, as a result, might have important clinical implications for interindividual variation in drug response.SIGNIFICANCE STATEMENT More than 90% of single nucleotide polymorhpisms (SNPs) that are associated with clinical phenotypes are located in non-coding regions of the genome. However, the mechanisms of action of many of those SNPs have not been elucidated and drugs may ‘unmask’ functional expression quantitative trail loci (eQTLs). In the current study, we used drugs that bind to the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and identified SNPs that were associated with interindividual variation in gene expression following drug exposure – termed pharmacogenomics (PGx)-eQTLs. Possibly of greater significance, those PGx-eQTL SNPs were outside of AHR binding sites indicating that they do not interrupt AHR DNA recognition. PGx-eQTLs such as those described here may have crucial implications for interindividual variation in drug. ER -