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Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

1 , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 6 , 8 , 9 , 10 , 4 , 11 , 4 , 12 , 13 , 14 , 15 , 7 , 12 , 16 , 17 , 18 , 19 , 20 , 21 , 1 , 2 , 22 , 23 , 24 , 1 , 2 , 25 , 2 , 26 , 27 , 6 , 8 , 28 , 28 , 29 , 30 , 31 , 32 , 31 , 5 , 6 , 7 , 33 , 33 , 11 , 34 , 35 , 35 , 36 , 37 , 38 , 39 , 4 , 4 , 4 , 40 , 41 , 42 , 43 , 43 , Welcome Trust Case Control Consortium, 12 , 44 , 45 , 46 , 47 , 12 , 48 , 13 , 49 , 13 , 50 , 14 , 51 , 52 , 53 , 54 , 55 , 56 , 14 , 14 , 7 , 45 , 46 , 57 , 58 , 12 , 59 , 44 , 60 , 61 , 62 , 63 , 17 , 64 , 64 , 9 , 9 , 9 , 65 , 66 , 67 , 19 , 20 , 68 , 2 , 19 , 68 , 2 , 19 , 68 , 17 , 19 , 9 , 17 , 18 , 61 , 55 , 69 , 70 , 7 , 14 , 51 , 12 , 45 , 46 , 71 , 4 , 11 , 4 , 72 , 73 , 74 , a , 3 , 75 , 76 , b , 6 , 8 , Membership of Wellcome Trust Case Control Consortium, Data and Analysis Group, DNA, Genotyping, Data QC and Informatics Group, Publications Committee

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      Abstract

      Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

      Abstract

      Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.

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      Most cited references 71

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      An Integrated Encyclopedia of DNA Elements in the Human Genome

      Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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        ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

        High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .
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          Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.

          We have developed an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). Reported TASs were common [median risk allele frequency 36%, interquartile range (IQR) 21%-53%] and were associated with modest effect sizes [median odds ratio (OR) 1.33, IQR 1.20-1.61]. Among 20 genomic annotation sets, reported TASs were significantly overrepresented only in nonsynonymous sites [OR = 3.9 (2.2-7.0), p = 3.5 x 10(-7)] and 5kb-promoter regions [OR = 2.3 (1.5-3.6), p = 3 x 10(-4)] compared to SNPs randomly selected from genotyping arrays. Although 88% of TASs were intronic (45%) or intergenic (43%), TASs were not overrepresented in introns and were significantly depleted in intergenic regions [OR = 0.44 (0.34-0.58), p = 2.0 x 10(-9)]. Only slightly more TASs than expected by chance were predicted to be in regions under positive selection [OR = 1.3 (0.8-2.1), p = 0.2]. This new online resource, together with bioinformatic predictions of the underlying functionality at trait/disease-associated loci, is well-suited to guide future investigations of the role of common variants in complex disease etiology.
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            Author and article information

            Affiliations
            [1 ]Department of Gerontology and Geriatrics, Leiden University Medical Center , Leiden 2300 RC, The Netherlands
            [2 ]The Netherlands Consortium for Healthy Ageing , Leiden 2300 RC, The Netherlands
            [3 ]Department of Cardiology, Leiden University Medical Center , Leiden 2300 RC, The Netherlands
            [4 ]Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee , Dundee DD1 9SY, UK
            [5 ]Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London , London EC1M6BQ, UK
            [6 ]NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London , London EC1M 6BQ, UK
            [7 ]Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center , Torrance, California 90502, USA
            [8 ]Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London , London EC1M6BQ, UK
            [9 ]Division of Preventive Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02215-1204, USA
            [10 ]Harvard Medical School , Boston, Massachusetts 02215, USA
            [11 ]Montreal Heart Institute, Universite de Montreal , Montreal H1T 1C8, Quebec, Canada
            [12 ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington , 98101 Seattle, Washington, USA
            [13 ]Department of Epidemiology, University of North Carolina , Chapel Hill, North Carolina 27599, USA
            [14 ]Department of Biostatistics, Boston University School of Public Health , Boston, Massachusetts 02215, USA
            [15 ]Department of Clinical Pharmacology, Vanderbilt University , Nashville, Tennessee 37240, USA
            [16 ]California Pacific Medical Center Research Institute , San Francisco, California 94107, USA
            [17 ]Icelandic Heart Association , IS-201 Kopavogur, Iceland
            [18 ]University of Iceland , IS-101 Reykjavik, Iceland
            [19 ]Department of Epidemiology, Erasmus Medical Center , 3000 CA Rotterdam, The Netherlands
            [20 ]Health Care Inspectorate , 2595 AN The Hague, The Netherlands
            [21 ]Framingham Heart Study (FHS) of the National Heart, Lung and Blood Institute, Cardiovascular Epidemiology and Human Genomics , Framingham, Massachusetts 01702, USA
            [22 ]Faculty of Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow , Glasgow G31 2ER, UK
            [23 ]Department of Pharmacology and Therapeutics, University College Cork , Cork 30, Ireland
            [24 ]Robertson Center for Biostatistics, University of Glasgow , Glasgow G12 8QQ, UK
            [25 ]Leyden Academy of Vitality and Ageing , 2333 AA Leiden, The Netherlands
            [26 ]Department of Molecular Epidemiology, Leiden University Medical Center , 2300 RC Leiden, The Netherlands
            [27 ]Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre , Glasgow G12 8QQ, UK
            [28 ]International Centre for Circulatory Health, Imperial College , London SW7 2AZ, UK
            [29 ]Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland , Dublin 2, Ireland
            [30 ]Beaumont Hospital , Dublin 9, Ireland
            [31 ]The Conway Institute, University College Dublin , Dublin 4, Ireland
            [32 ]School of Medicine and Medical Sciences, University College Dublin , Dublin 4, Ireland
            [33 ]Department of Genome Sciences, University of Washington , Seattle, Washington 98101, USA
            [34 ]Department of Cardiology, Academic Medical Center , 1100 DD Amsterdam, The Netherlands
            [35 ]Department of Vascular Medicine, Academic Medical Center , 1100 DD Amsterdam, The Netherlands
            [36 ]University of Edinburgh , Edinburgh EH9 3JR, UK
            [37 ]University College, London WC1E 6BT, UK
            [38 ]University of Oxford , Oxford OX1 2JD, UK
            [39 ]Cardiovascular Research Group, School of Biosciences, University of Manchester , Manchester M13 9NT, UK
            [40 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road , Headington, Oxford OX3 7LJ, UK
            [41 ]Wellcome Trust Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford OX3 7BN, UK
            [42 ]Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road , Headington, Oxford OX3 7LJ, UK
            [43 ]Department of Clinical Sciences/Diabetes & Endocrinology, Lund University , Malmo 205 02, Sweden
            [44 ]Department of Biostatistics, University of Washington , 98115 Seattle, Washington, USA
            [45 ]Department of Epidemiology, University of Washington , Seattle, Washington 98195, USA
            [46 ]Group Health Research Institute, Group Health Cooperative , Seattle, Washington 98101, USA
            [47 ]Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development , Seattle, Washington 98101, USA
            [48 ]Department of Statistic, University of Auckland , Auckland 1142, New Zealand
            [49 ]Department of Medicine, University of North Carolina , Chapel Hill, North Carolina 27599, USA
            [50 ]Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston , Houston, Texas 77030, USA
            [51 ]NHLBI Framingham Heart Study , Framingham, Massachusetts 01701, USA
            [52 ]Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts 02115, USA
            [53 ]National Heart, Lung and Blood Institute , Bethesda, Maryland 20892, USA
            [54 ]Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, and the Framingham Heart Study , Framingham, Massachusetts 01701, USA
            [55 ]Department of Biomedical Informatics, Vanderbilt University , Nashville, Tennessee 37240, USA
            [56 ]Department of Internal Medicine, Center for IMAGENETICS, Sanford Healthcare , Fargo, North Dakota, 58104 USA
            [57 ]Cardiovascular Health Research Unit, University of Washington , Seattle, Washington 98101, USA
            [58 ]Department of Cardiology, Johns Hopkins University , Baltimore, Maryland 21218, USA
            [59 ]Division of Cardiology, Harborview Medical Center, University of Washington , Seattle 98101, Washington, USA
            [60 ]Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, USA
            [61 ]Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, USA
            [62 ]Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, USA
            [63 ]Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, USA
            [64 ]Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health , 7201 Wisconsin Avenue, Bethesda, Maryland 20892, USA
            [65 ]Personalised Healthcare and Biomarkers, AstraZeneca , Alderley Park SK10 4TG, UK
            [66 ]AstraZeneca Research and Development , 481 83 Mölndal, Sweden
            [67 ]Unit of Occupational and Environmental Medicine, University of Gothenburg , 405 30 Gothenburg, Sweden
            [68 ]Department of Internal Medicine, Erasmus Medical Center , 3000 CA Rotterdam, The Netherlands
            [69 ]Department of Medicine, Vanderbilt University , Vanderbilt, Tennessee 37240, USA
            [70 ]Department of Medicine, Baylor College of Medicine , Houston, Texas 77030, USA
            [71 ]Department of Health Services, University of Washington , Seattle, Washington 98101, USA
            [72 ]Department of Public Health, University of Dundee , Dundee DD1 9SY, UK
            [73 ]Barts and the London School of Medicine and Dentistry, Queen Mary University of London , London E1 2AT, UK
            [74 ]Children’s Hospital Oakland Research Institute , Oakland, California 94609, USA
            [75 ]Durrer Center for Cardiogenetic Research , 1105 AZ Amsterdam, The Netherlands
            [76 ]Interuniversity Cardiology Institute of the Netherlands , 3511 GC Utrecht, The Netherlands
            [77 ]Wellcome Trust Centre for Human Genetics , Roosevelt Drive, Oxford, UK
            [78 ]Department of Statistics, University of Oxford , Oxford, UK
            [79 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus , Hinxton, Cambridge, UK
            [80 ]Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia , 100 Roberts Road, Subiaco, Western Australia, Australia
            [81 ]Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine , Cambridge, UK
            [82 ]Department of Psychosis Studies, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and The South London and Maudsley NHS Foundation Trust , Denmark Hill, London, UK
            [83 ]University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland , Brisbane, Queensland, Australia
            [84 ]Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine , London, UK
            [85 ]Department of Epidemiology and Public Health, University College London , London, UK
            [86 ]Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin , Dublin, Ireland
            [87 ]Molecular and Physiological Sciences, The Wellcome Trust , London, UK
            [88 ]Centre for Digestive Diseases, Queen Mary University of London , London, UK
            [89 ]Digestive Diseases Centre, Leicester Royal Infirmary , Leicester, UK
            [90 ]Department of Clinical Pharmacology, Old Road Campus, University of Oxford, Oxford, UK
            [91 ]Clinical Neurosciences, St George’s University of London , London, UK
            [92 ]King’s College London, Department of Medical and Molecular Genetics, School of Medicine, Guy’s Hospital , London, UK
            [93 ]Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School , Dundee, UK
            [94 ]King’s College London Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry , Denmark Hill, London, UK
            [95 ]University of Cambridge, Department of Clinical Neurosciences, Addenbrooke’s Hospital , Cambridge, UK
            [96 ]NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology , London, UK
            [97 ]Department of Molecular Neuroscience, Institute of Neurology , Queen Square, London, UK
            [98 ]Oxford Centre for Diabetes, Endocrinology and Metabolism (ICDEM), Churchill Hospital , Oxford, UK
            Author notes
            [*]

            These authors contributed equally

            [†]

            Members of Welcome Trust Case Control Consortium are listed at the end of the paper

            [‡]

            These authors jointly supervised the work

            [∥]

            Management Committee:

            Journal
            Nat Commun
            Nat Commun
            Nature Communications
            Nature Pub. Group
            2041-1723
            28 October 2014
            : 5
            25350695 4220464 ncomms6068 10.1038/ncomms6068
            Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

            This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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