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dc.contributor.authorSchmidt, AFen_US
dc.contributor.authorHolmes, MVen_US
dc.contributor.authorPreiss, Den_US
dc.contributor.authorSwerdlow, DIen_US
dc.contributor.authorDenaxas, Sen_US
dc.contributor.authorFatemifar, Gen_US
dc.contributor.authorFaraway, Ren_US
dc.contributor.authorFinan, Cen_US
dc.contributor.authorValentine, Den_US
dc.contributor.authorFairhurst-Hunter, Zen_US
dc.contributor.authorHartwig, FPen_US
dc.contributor.authorHorta, BLen_US
dc.contributor.authorHypponen, Een_US
dc.contributor.authorPower, Cen_US
dc.contributor.authorMoldovan, Men_US
dc.contributor.authorvan Iperen, Een_US
dc.contributor.authorHovingh, Ken_US
dc.contributor.authorDemuth, Ien_US
dc.contributor.authorNorman, Ken_US
dc.contributor.authorSteinhagen-Thiessen, Een_US
dc.contributor.authorDemuth, Jen_US
dc.contributor.authorBertram, Len_US
dc.contributor.authorLill, CMen_US
dc.contributor.authorCoassin, Sen_US
dc.contributor.authorWilleit, Jen_US
dc.contributor.authorKiechl, Sen_US
dc.contributor.authorWilleit, Ken_US
dc.contributor.authorMason, Den_US
dc.contributor.authorWright, Jen_US
dc.contributor.authorMorris, Ren_US
dc.contributor.authorWanamethee, Gen_US
dc.contributor.authorWhincup, Pen_US
dc.contributor.authorBen-Shlomo, Yen_US
dc.contributor.authorMcLachlan, Sen_US
dc.contributor.authorPrice, JFen_US
dc.contributor.authorKivimaki, Men_US
dc.contributor.authorWelch, Cen_US
dc.contributor.authorSanchez-Galvez, Aen_US
dc.contributor.authorMarques-Vidal, Pen_US
dc.contributor.authorNicolaides, Aen_US
dc.contributor.authorPanayiotou, AGen_US
dc.contributor.authorOnland-Moret, NCen_US
dc.contributor.authorvan der Schouw, YTen_US
dc.contributor.authorMatullo, Gen_US
dc.contributor.authorFiorito, Gen_US
dc.contributor.authorGuarrera, Sen_US
dc.contributor.authorSacerdote, Cen_US
dc.contributor.authorWareham, NJen_US
dc.contributor.authorLangenberg, Cen_US
dc.contributor.authorScott, RAen_US
dc.contributor.authorLuan, Jen_US
dc.contributor.authorBobak, Men_US
dc.contributor.authorMalyutina, Sen_US
dc.contributor.authorPająk, Aen_US
dc.contributor.authorKubinova, Ren_US
dc.contributor.authorTamosiunas, Aen_US
dc.contributor.authorPikhart, Hen_US
dc.contributor.authorGrarup, Nen_US
dc.contributor.authorPedersen, Oen_US
dc.contributor.authorHansen, Ten_US
dc.contributor.authorLinneberg, Aen_US
dc.contributor.authorJess, Ten_US
dc.contributor.authorCooper, Jen_US
dc.contributor.authorHumphries, SEen_US
dc.contributor.authorBrilliant, Men_US
dc.contributor.authorKitchner, Ten_US
dc.contributor.authorHakonarson, Hen_US
dc.contributor.authorCarrell, DSen_US
dc.contributor.authorMcCarty, CAen_US
dc.contributor.authorLester, KHen_US
dc.contributor.authorLarson, EBen_US
dc.contributor.authorCrosslin, DRen_US
dc.contributor.authorde Andrade, Men_US
dc.contributor.authorRoden, DMen_US
dc.contributor.authorDenny, JCen_US
dc.contributor.authorCarty, Cen_US
dc.contributor.authorHancock, Sen_US
dc.contributor.authorAttia, Jen_US
dc.contributor.authorHolliday, Een_US
dc.contributor.authorScott, Ren_US
dc.contributor.authorSchofield, Pen_US
dc.contributor.authorO'Donnell, Men_US
dc.contributor.authorYusuf, Sen_US
dc.contributor.authorChong, Men_US
dc.contributor.authorPare, Gen_US
dc.contributor.authorvan der Harst, Pen_US
dc.contributor.authorSaid, MAen_US
dc.contributor.authorEppinga, RNen_US
dc.contributor.authorVerweij, Nen_US
dc.contributor.authorSnieder, Hen_US
dc.contributor.authorLifelines Cohort authorsen_US
dc.contributor.authorChristen, Ten_US
dc.contributor.authorMook-Kanamori, DOen_US
dc.contributor.authorICBP Consortiumen_US
dc.contributor.authorGustafsson, Sen_US
dc.contributor.authorLind, Len_US
dc.contributor.authorIngelsson, Een_US
dc.contributor.authorPazoki, Ren_US
dc.contributor.authorFranco, Oen_US
dc.contributor.authorHofman, Aen_US
dc.contributor.authorUitterlinden, Aen_US
dc.contributor.authorDehghan, Aen_US
dc.contributor.authorTeumer, Aen_US
dc.contributor.authorBaumeister, Sen_US
dc.contributor.authorDörr, Men_US
dc.contributor.authorLerch, MMen_US
dc.contributor.authorVölker, Uen_US
dc.contributor.authorVölzke, Hen_US
dc.contributor.authorWard, Jen_US
dc.contributor.authorPell, JPen_US
dc.contributor.authorMeade, Ten_US
dc.contributor.authorChristophersen, IEen_US
dc.contributor.authorMaitland-van der Zee, AHen_US
dc.contributor.authorBaranova, EVen_US
dc.contributor.authorYoung, Ren_US
dc.contributor.authorFord, Ien_US
dc.contributor.authorCampbell, Aen_US
dc.contributor.authorPadmanabhan, Sen_US
dc.contributor.authorBots, MLen_US
dc.contributor.authorGrobbee, DEen_US
dc.contributor.authorFroguel, Pen_US
dc.contributor.authorThuillier, Den_US
dc.contributor.authorRoussel, Ren_US
dc.contributor.authorBonnefond, Aen_US
dc.contributor.authorCariou, Ben_US
dc.contributor.authorSmart, Men_US
dc.contributor.authorBao, Yen_US
dc.contributor.authorKumari, Men_US
dc.contributor.authorMahajan, Aen_US
dc.contributor.authorHopewell, JCen_US
dc.contributor.authorSeshadri, Sen_US
dc.contributor.authorMETASTROKE Consortium of the ISGCen_US
dc.contributor.authorDale, Cen_US
dc.contributor.authorCosta, RPEen_US
dc.contributor.authorRidker, PMen_US
dc.contributor.authorChasman, DIen_US
dc.contributor.authorReiner, APen_US
dc.contributor.authorRitchie, MDen_US
dc.contributor.authorLange, LAen_US
dc.contributor.authorCornish, AJen_US
dc.contributor.authorDobbins, SEen_US
dc.contributor.authorHemminki, Ken_US
dc.contributor.authorKinnersley, Ben_US
dc.contributor.authorSanson, Men_US
dc.contributor.authorLabreche, Ken_US
dc.contributor.authorSimon, Men_US
dc.contributor.authorBondy, Men_US
dc.contributor.authorLaw, Pen_US
dc.contributor.authorSpeedy, Hen_US
dc.contributor.authorAllan, Jen_US
dc.contributor.authorLi, Nen_US
dc.contributor.authorWent, Men_US
dc.contributor.authorWeinhold, Nen_US
dc.contributor.authorMorgan, Gen_US
dc.contributor.authorSonneveld, Pen_US
dc.contributor.authorNilsson, Ben_US
dc.contributor.authorGoldschmidt, Hen_US
dc.contributor.authorSud, Aen_US
dc.contributor.authorEngert, Aen_US
dc.contributor.authorHansson, Men_US
dc.contributor.authorHemingway, Hen_US
dc.contributor.authorAsselbergs, FWen_US
dc.contributor.authorPatel, RSen_US
dc.contributor.authorKeating, BJen_US
dc.contributor.authorSattar, Nen_US
dc.contributor.authorHoulston, Ren_US
dc.contributor.authorCasas, JPen_US
dc.contributor.authorHingorani, ADen_US
dc.date.accessioned2020-03-02T10:36:58Z
dc.date.issued2019-10-29en_US
dc.identifier.citationBMC cardiovascular disorders, 2019, 19 (1), pp. 240 - ?en_US
dc.identifier.issn1471-2261en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3521
dc.identifier.eissn1471-2261en_US
dc.identifier.doi10.1186/s12872-019-1187-zen_US
dc.description.abstractBACKGROUND:We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS:Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS:The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS:Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.en_US
dc.formatElectronicen_US
dc.format.extent240 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectLifelines Cohort authorsen_US
dc.subjectICBP Consortiumen_US
dc.subjectMETASTROKE Consortium of the ISGCen_US
dc.subjectHumansen_US
dc.subjectBrain Ischemiaen_US
dc.subjectMyocardial Infarctionen_US
dc.subjectAnticholesteremic Agentsen_US
dc.subjectSerine Proteinase Inhibitorsen_US
dc.subjectTreatment Outcomeen_US
dc.subjectRisk Assessmenten_US
dc.subjectRisk Factorsen_US
dc.subjectDown-Regulationen_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.subjectDyslipidemiasen_US
dc.subjectCholesterol, LDLen_US
dc.subjectRandomized Controlled Trials as Topicen_US
dc.subjectStrokeen_US
dc.subjectGenome-Wide Association Studyen_US
dc.subjectBiomarkersen_US
dc.subjectProprotein Convertase 9en_US
dc.titlePhenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-08-19en_US
rioxxterms.versionofrecord10.1186/s12872-019-1187-zen_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2019-10-29en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfBMC cardiovascular disordersen_US
pubs.issue1en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Molecular & Population Genetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.publication-statusPublisheden_US
pubs.volume19en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMolecular & Population Geneticsen_US
dc.contributor.icrauthorSud, Amiten_US
dc.contributor.icrauthorLaw, Philipen_US
dc.contributor.icrauthorKinnersley, Benjaminen_US


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