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      Is Open Access

      Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity

      review-article
      , , *
      Pharmacology & Therapeutics
      Pergamon Press
      5caC, 5- Carboxylcytosine, 5fC, 5- Formylcytosine, 5hmC, 5-hydroxymethylcytosine, ABC-HSS, Abacavir hypersensitivity syndrome., ALL, Acute lymphoblastic leukemia, CAT, Catalase, CFTR, Cystic fibrosis transmembrane conductance regulator, ChIP, Chromatin immunoprecipitation, CNVs, Copy number variations, CPIC, Clinical Pharmacogenetics Implementation Consortium, DHR, Drug hypersensitivity reactions, DIHS, Drug-induced hypersensitivity syndrome., DILI, Drug-induced liver injury, DNMTs, DNA methyltransferases, DPWG, Dutch Pharmacogenetics Working Group, DRESS, Drug rash with eosinophilia and systemic symptoms, eQTL, Quantitative trait locus, GPCR, G-protein coupled receptor, GST, Glutathione-S-transferase, HDACs, Histone deacetylases, MAF, Minor allele frequencies, MPE, Maculopapular exanthema, MS, Multiple sclerosis, PM, Poor metabolism, oxBS-seq, Oxidative bisulfite sequencing, PRC2, Polycomb repressive complex 2, PTMs, Posttranslational modifications, RA, Retinoic acid, SCAR, Severe cutaneous adverse reaction, SJS, Stevens-Johnson syndrome, SNVs, Single nucleotide variations, TAB-Seq, TET-assisted bisulfite sequencing, TEN, Toxic epidermal necrolysis, UM, Ultrarapid metabolism

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          Abstract

          Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.

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          Most cited references285

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          High-resolution mapping and characterization of open chromatin across the genome.

          Mapping DNase I hypersensitive (HS) sites is an accurate method of identifying the location of genetic regulatory elements, including promoters, enhancers, silencers, insulators, and locus control regions. We employed high-throughput sequencing and whole-genome tiled array strategies to identify DNase I HS sites within human primary CD4+ T cells. Combining these two technologies, we have created a comprehensive and accurate genome-wide open chromatin map. Surprisingly, only 16%-21% of the identified 94,925 DNase I HS sites are found in promoters or first exons of known genes, but nearly half of the most open sites are in these regions. In conjunction with expression, motif, and chromatin immunoprecipitation data, we find evidence of cell-type-specific characteristics, including the ability to identify transcription start sites and locations of different chromatin marks utilized in these cells. In addition, and unexpectedly, our analyses have uncovered detailed features of nucleosome structure.
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            DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.

            Mammals use DNA methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females. The establishment of patterns of DNA methylation during gametogenesis depends in part on DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferases DNMT3A and DNMT3B. The main proteins that interact in vivo with the product of an epitope-tagged allele of the endogenous Dnmt3L gene were identified by mass spectrometry as DNMT3A2, DNMT3B and the four core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.
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              Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome.

              The study of 5-hydroxylmethylcytosines (5hmC) has been hampered by the lack of a method to map it at single-base resolution on a genome-wide scale. Affinity purification-based methods cannot precisely locate 5hmC nor accurately determine its relative abundance at each modified site. We here present a genome-wide approach, Tet-assisted bisulfite sequencing (TAB-Seq), that when combined with traditional bisulfite sequencing can be used for mapping 5hmC at base resolution and quantifying the relative abundance of 5hmC as well as 5mC. Application of this method to embryonic stem cells not only confirms widespread distribution of 5hmC in the mammalian genome but also reveals sequence bias and strand asymmetry at 5hmC sites. We observe high levels of 5hmC and reciprocally low levels of 5mC near but not on transcription factor-binding sites. Additionally, the relative abundance of 5hmC varies significantly among distinct functional sequence elements, suggesting different mechanisms for 5hmC deposition and maintenance. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Pharmacol Ther
                Pharmacol. Ther
                Pharmacology & Therapeutics
                Pergamon Press
                0163-7258
                1879-016X
                1 May 2019
                May 2019
                : 197
                : 122-152
                Affiliations
                Department of Physiology and Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden
                Author notes
                [* ]Corresponding author. magnus.ingelman-sundberg@ 123456ki.se
                Article
                S0163-7258(19)30008-7
                10.1016/j.pharmthera.2019.01.002
                6527860
                30677473
                3811cd38-91f1-467a-9306-c59776adf994
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Pharmacology & Pharmaceutical medicine
                5cac, 5- carboxylcytosine,5fc, 5- formylcytosine,5hmc, 5-hydroxymethylcytosine,abc-hss, abacavir hypersensitivity syndrome.,all, acute lymphoblastic leukemia,cat, catalase,cftr, cystic fibrosis transmembrane conductance regulator,chip, chromatin immunoprecipitation,cnvs, copy number variations,cpic, clinical pharmacogenetics implementation consortium,dhr, drug hypersensitivity reactions,dihs, drug-induced hypersensitivity syndrome.,dili, drug-induced liver injury,dnmts, dna methyltransferases,dpwg, dutch pharmacogenetics working group,dress, drug rash with eosinophilia and systemic symptoms,eqtl, quantitative trait locus,gpcr, g-protein coupled receptor,gst, glutathione-s-transferase,hdacs, histone deacetylases,maf, minor allele frequencies,mpe, maculopapular exanthema,ms, multiple sclerosis,pm, poor metabolism,oxbs-seq, oxidative bisulfite sequencing,prc2, polycomb repressive complex 2,ptms, posttranslational modifications,ra, retinoic acid,scar, severe cutaneous adverse reaction,sjs, stevens-johnson syndrome,snvs, single nucleotide variations,tab-seq, tet-assisted bisulfite sequencing,ten, toxic epidermal necrolysis,um, ultrarapid metabolism

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