Schmidt, Amand FAmand FSchmidtHolmes, Michael VMichael VHolmesPreiss, DavidDavidPreissSwerdlow, Daniel IDaniel ISwerdlowDenaxas, SpirosSpirosDenaxasFatemifar, GhazalehGhazalehFatemifarFaraway, RupertRupertFarawayFinan, ChrisChrisFinanValentine, DennisDennisValentineFairhurst-Hunter, ZammyZammyFairhurst-HunterHartwig, Fernando PiresFernando PiresHartwigHorta, Bernardo LessaBernardo LessaHortaHypponen, ElinaElinaHypponenPower, ChristineChristinePowerMoldovan, MaxMaxMoldovanvan Iperen, ErikErikvan IperenHovingh, KeesKeesHovinghDemuth, IljaIljaDemuthNorman, KristinaKristinaNormanSteinhagen-Thiessen, ElisabethElisabethSteinhagen-ThiessenDemuth, JuriJuriDemuthBertram, LarsLarsBertramLill, Christina MChristina MLillCoassin, StefanStefanCoassinWilleit, JohannJohannWilleitKiechl, StefanStefanKiechlWilleit, Karin ChristineKarin ChristineWilleitMason, DanDanMasonWright, JohnJohnWrightMorris, RichardRichardMorrisWanamethee, GoyaGoyaWanametheeWhincup, PeterPeterWhincupBen-Shlomo, YoavYoavBen-ShlomoMcLachlan, StelaStelaMcLachlanPrice, Jackie FJackie FPriceKivimaki, MikaMikaKivimakiWelch, CatherineCatherineWelchSanchez-Galvez, AdelaidaAdelaidaSanchez-GalvezMarques-Vidal, PedroPedroMarques-VidalNicolaides, AndrewAndrewNicolaidesPanayiotou, Andrie GAndrie GPanayiotouOnland-Moret, N CharlotteN CharlotteOnland-Moretvan der Schouw, Yvonne TYvonne Tvan der SchouwMatullo, GiuseppeGiuseppeMatulloFiorito, GiovanniGiovanniFioritoGuarrera, SimonettaSimonettaGuarreraSacerdote, CarlottaCarlottaSacerdoteWareham, Nicholas JNicholas JWarehamLangenberg, ClaudiaClaudiaLangenbergScott, Robert ARobert AScottLuan, Jian'anJian'anLuanBobak, MartinMartinBobakMalyutina, SofiaSofiaMalyutinaPająk, AndrzejAndrzejPająkKubinova, RuzenaRuzenaKubinovaTamosiunas, AbdonasAbdonasTamosiunasPikhart, HynekHynekPikhartGrarup, NielsNielsGrarupPedersen, OlufOlufPedersenHansen, TorbenTorbenHansenLinneberg, AllanAllanLinnebergJess, TineTineJessCooper, JackieJackieCooperHumphries, Steve ESteve EHumphriesBrilliant, MurrayMurrayBrilliantKitchner, TerrieTerrieKitchnerHakonarson, HakonHakonHakonarsonCarrell, David SDavid SCarrellMcCarty, Catherine ACatherine AMcCartyLester, Kirchner HKirchner HLesterLarson, Eric BEric BLarsonCrosslin, David RDavid RCrosslinde Andrade, MarizaMarizade AndradeRoden, Dan MDan MRodenDenny, Joshua CJoshua CDennyCarty, CaraCaraCartyHancock, StephenStephenHancockAttia, JohnJohnAttiaHolliday, ElizabethElizabethHollidayScott, RodneyRodneyScottSchofield, PeterPeterSchofieldO'Donnell, MartinMartinO'DonnellYusuf, SalimSalimYusufChong, MichaelMichaelChongPare, GuillaumeGuillaumeParevan der Harst, PimPimvan der HarstSaid, M AbdullahM AbdullahSaidEppinga, Ruben NRuben NEppingaVerweij, NiekNiekVerweijSnieder, HaroldHaroldSniederChristen, TimTimChristenMook-Kanamori, D OD OMook-KanamoriGustafsson, StefanStefanGustafssonLind, LarsLarsLindIngelsson, ErikErikIngelssonPazoki, RahaRahaPazokiFranco, OscarOscarFrancoHofman, AlbertAlbertHofmanUitterlinden, AndreAndreUitterlindenDehghan, AbbasAbbasDehghanTeumer, AlexanderAlexanderTeumerBaumeister, SebastianSebastianBaumeisterDörr, MarcusMarcusDörrLerch, Markus MMarkus MLerchVölker, UweUweVölkerVölzke, HenryHenryVölzkeWard, JoeyJoeyWardPell, Jill PJill PPellMeade, TomTomMeadeChristophersen, Ingrid EIngrid EChristophersenMaitland-van der Zee, Anke HAnke HMaitland-van der ZeeBaranova, Ekaterina VEkaterina VBaranovaYoung, RobinRobinYoungFord, IanIanFordCampbell, ArchieArchieCampbellPadmanabhan, SandoshSandoshPadmanabhanBots, Michiel LMichiel LBotsGrobbee, Diederick EDiederick EGrobbeeFroguel, PhilippePhilippeFroguelThuillier, DorothéeDorothéeThuillierRoussel, RonanRonanRousselBonnefond, AmélieAmélieBonnefondCariou, BertrandBertrandCariouSmart, MelissaMelissaSmartBao, YanchunYanchunBaoKumari, MeenaMeenaKumariMahajan, AnubhaAnubhaMahajanHopewell, Jemma CJemma CHopewellSeshadri, SudhaSudhaSeshadriDale, CarolineCarolineDaleCosta, Rui Providencia ERui Providencia ECostaRidker, Paul MPaul MRidkerChasman, Daniel IDaniel IChasmanReiner, Alex PAlex PReinerRitchie, Marylyn DMarylyn DRitchieLange, Leslie ALeslie ALangeCornish, Alex JAlex JCornishDobbins, Sara ESara EDobbinsHemminki, KariKariHemminkiKinnersley, BenBenKinnersleySanson, MarcMarcSansonLabreche, KarimKarimLabrecheSimon, MatthiasMatthiasSimonBondy, MelissaMelissaBondyLaw, PhilipPhilipLawSpeedy, HelenHelenSpeedyAllan, JamesJamesAllanLi, NiNiLiWent, MollyMollyWentWeinhold, NielsNielsWeinholdMorgan, GarethGarethMorganSonneveld, PieterPieterSonneveldNilsson, BjörnBjörnNilssonGoldschmidt, HartmutHartmutGoldschmidtSud, AmitAmitSudEngert, AndreasAndreasEngertHansson, MarkusMarkusHanssonHemingway, HarryHarryHemingwayAsselbergs, Folkert WFolkert WAsselbergsPatel, Riyaz SRiyaz SPatelKeating, Brendan JBrendan JKeatingSattar, NaveedNaveedSattarHoulston, RichardRichardHoulstonCasas, Juan PJuan PCasasHingorani, Aroon DAroon DHingorani2024-10-282024-10-282019-10-29https://boris-portal.unibe.ch/handle/20.500.12422/184844BACKGROUND 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.enGenetic association studies LDL-cholesterol Mendelian randomisation Phenome-wide association scan600 - Technology::610 - Medicine & healtharticle10.7892/boris.1373293166492010.1186/s12872-019-1187-z