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Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression

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 iden...

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Autores principales: Neavin, Drew R., Lee, Jeong-Heon, Liu, Duan, Ye, Zhenqing, Li, Hu, Wang, Liewei, Ordog, Tamas, Weinshilboum, Richard M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Pharmacology and Experimental Therapeutics 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184190/
https://www.ncbi.nlm.nih.gov/pubmed/31292129
http://dx.doi.org/10.1124/dmd.119.087312
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author Neavin, Drew R.
Lee, Jeong-Heon
Liu, Duan
Ye, Zhenqing
Li, Hu
Wang, Liewei
Ordog, Tamas
Weinshilboum, Richard M.
author_facet Neavin, Drew R.
Lee, Jeong-Heon
Liu, Duan
Ye, Zhenqing
Li, Hu
Wang, Liewei
Ordog, Tamas
Weinshilboum, Richard M.
author_sort Neavin, Drew R.
collection PubMed
description 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 that may have important pharmacotherapeutic implications. In the present study, we integrated chromatin immunoprecipitation-seq with RNA-seq and SNP genotype data for a panel of lymphoblastoid cell lines 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, whereas others displayed SNP-by-ligand–dependent effects in just one cell type. Furthermore, 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 polymorphisms (SNPs) that are associated with clinical phenotypes are located in noncoding 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 pharmacogenomic (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 in this work may have crucial implications for interindividual variation in drug.
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spelling pubmed-71841902020-05-06 Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression Neavin, Drew R. Lee, Jeong-Heon Liu, Duan Ye, Zhenqing Li, Hu Wang, Liewei Ordog, Tamas Weinshilboum, Richard M. Drug Metab Dispos Articles 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 that may have important pharmacotherapeutic implications. In the present study, we integrated chromatin immunoprecipitation-seq with RNA-seq and SNP genotype data for a panel of lymphoblastoid cell lines 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, whereas others displayed SNP-by-ligand–dependent effects in just one cell type. Furthermore, 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 polymorphisms (SNPs) that are associated with clinical phenotypes are located in noncoding 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 pharmacogenomic (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 in this work may have crucial implications for interindividual variation in drug. The American Society for Pharmacology and Experimental Therapeutics 2019-09 2019-09 /pmc/articles/PMC7184190/ /pubmed/31292129 http://dx.doi.org/10.1124/dmd.119.087312 Text en Copyright © 2019 by The Author(s) http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the CC BY-NC Attribution 4.0 International license (http://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Articles
Neavin, Drew R.
Lee, Jeong-Heon
Liu, Duan
Ye, Zhenqing
Li, Hu
Wang, Liewei
Ordog, Tamas
Weinshilboum, Richard M.
Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression
title Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression
title_full Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression
title_fullStr Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression
title_full_unstemmed Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression
title_short Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression
title_sort single nucleotide polymorphisms at a distance from aryl hydrocarbon receptor (ahr) binding sites influence ahr ligand–dependent gene expression
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184190/
https://www.ncbi.nlm.nih.gov/pubmed/31292129
http://dx.doi.org/10.1124/dmd.119.087312
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