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dc.contributor.authorScott, Roberten
dc.contributor.authorFreitag, Daniel Fen
dc.contributor.authorLi, Lien
dc.contributor.authorChu, Audrey Yen
dc.contributor.authorSurendran, Praveenen
dc.contributor.authorYoung, Robinen
dc.contributor.authorGrarup, Nielsen
dc.contributor.authorStancáková, Alenaen
dc.contributor.authorChen, Yuningen
dc.contributor.authorVarga, Tibor Ven
dc.contributor.authorYaghootkar, Haniehen
dc.contributor.authorLuan, Jian'anen
dc.contributor.authorZhao, Jing Huaen
dc.contributor.authorWillems, Saraen
dc.contributor.authorWessel, Jenniferen
dc.contributor.authorWang, Shuaien
dc.contributor.authorMaruthur, Nisaen
dc.contributor.authorMichailidou, Kyriakien
dc.contributor.authorPirie, Ailithen
dc.contributor.authorvan, der Lee Sven Jen
dc.contributor.authorGillson, Christopheren
dc.contributor.authorAl, Olama Ali Aminen
dc.contributor.authorAmouyel, Philippeen
dc.contributor.authorArriola, Larraitzen
dc.contributor.authorArveiler, Dominiqueen
dc.contributor.authorAviles-Olmos, Iciaren
dc.contributor.authorBalkau, Beverleyen
dc.contributor.authorBarricarte, Aurelioen
dc.contributor.authorBarroso, Inesen
dc.contributor.authorGarcia, Sara Benllochen
dc.contributor.authorBis, Joshua Cen
dc.contributor.authorBlankenberg, Stefanen
dc.contributor.authorBoehnke, Michaelen
dc.contributor.authorBoeing, Heineren
dc.contributor.authorBoerwinkle, Ericen
dc.contributor.authorBorecki, Ingrid Ben
dc.contributor.authorBork-Jensen, Jetteen
dc.contributor.authorBowden, Sarahen
dc.contributor.authorCaldas, Carlosen
dc.contributor.authorCaslake, Murielen
dc.contributor.authorCupples, L Adrienneen
dc.contributor.authorCruchaga, Carlosen
dc.contributor.authorCzajkowski, Jaceken
dc.contributor.authorden, Hoed Marcelen
dc.contributor.authorDunn, Janet Aen
dc.contributor.authorEarl, Helenaen
dc.contributor.authorEhret, Georg Ben
dc.contributor.authorFerrannini, Eleen
dc.contributor.authorFerrieres, Jeanen
dc.contributor.authorFoltynie, Thomasen
dc.contributor.authorFord, Ianen
dc.contributor.authorForouhi, Nitaen
dc.contributor.authorGianfagna, Francescoen
dc.contributor.authorGonzalez, Carlosen
dc.contributor.authorGrioni, Saraen
dc.contributor.authorHiller, Louiseen
dc.contributor.authorJansson, Jan-Håkanen
dc.contributor.authorJørgensen, Marit Een
dc.contributor.authorJukema, J Wouteren
dc.contributor.authorKaaks, Rudolfen
dc.contributor.authorKee, Franken
dc.contributor.authorKerrison, Nicola Den
dc.contributor.authorKey, Timothy Jen
dc.contributor.authorKontto, Jukkaen
dc.contributor.authorKote-Jarai, Zsofiaen
dc.contributor.authorKraja, Aldi Ten
dc.contributor.authorKuulasmaa, Karien
dc.contributor.authorKuusisto, Johannaen
dc.contributor.authorLinneberg, Allanen
dc.contributor.authorLiu, Chunyuen
dc.contributor.authorMarenne, Gaëlleen
dc.contributor.authorMohlke, Karen Len
dc.contributor.authorMorris, Andrew Pen
dc.contributor.authorMuir, Kennethen
dc.contributor.authorMüller-Nurasyid, Martinaen
dc.contributor.authorMunroe, Patricia Ben
dc.contributor.authorNavarro, Carmenen
dc.contributor.authorNielsen, Sune Fen
dc.contributor.authorNilsson, Peter Men
dc.contributor.authorNordestgaard, Børge Gen
dc.contributor.authorPackard, Chris Jen
dc.contributor.authorPalli, Domenicoen
dc.contributor.authorPanico, Salvatoreen
dc.contributor.authorPeloso, Gina Men
dc.contributor.authorPerola, Markusen
dc.contributor.authorPeters, Annetteen
dc.contributor.authorPoole, Christopher Jen
dc.contributor.authorQuirós, J Ramónen
dc.contributor.authorRolandsson, Oloven
dc.contributor.authorSacerdote, Carlottaen
dc.contributor.authorSalomaa, Veikkoen
dc.contributor.authorSánchez, María-Joséen
dc.contributor.authorSattar, Naveeden
dc.contributor.authorSharp, Stephenen
dc.contributor.authorSims, Rebeccaen
dc.contributor.authorSlimani, Nadiaen
dc.contributor.authorSmith, Jennifer Aen
dc.contributor.authorThompson, Deborahen
dc.contributor.authorTrompet, Stellaen
dc.contributor.authorTumino, Rosarioen
dc.contributor.authorvan, der A Daphne Len
dc.contributor.authorvan, der Schouw Yvonne Ten
dc.contributor.authorVirtamo, Jarmoen
dc.contributor.authorWalker, Marken
dc.contributor.authorWalter, Klaudiaen
dc.contributor.authorAbraham, Jeanen
dc.contributor.authorAmundadottir, Laufey Ten
dc.contributor.authorAponte, Jennifer Len
dc.contributor.authorButterworth, Adamen
dc.contributor.authorDupuis, Joséeen
dc.contributor.authorEaston, Douglasen
dc.contributor.authorEeles, Rosalind Aen
dc.contributor.authorErdmann, Jeanetteen
dc.contributor.authorFranks, Paul Wen
dc.contributor.authorFrayling, Timothy Men
dc.contributor.authorHansen, Torbenen
dc.contributor.authorHowson, Joannaen
dc.contributor.authorJørgensen, Torbenen
dc.contributor.authorKooner, Jaspalen
dc.contributor.authorLaakso, Markkuen
dc.contributor.authorLangenberg, Claudiaen
dc.contributor.authorMcCarthy, Mark Ien
dc.contributor.authorPankow, James Sen
dc.contributor.authorPedersen, Olufen
dc.contributor.authorRiboli, Elioen
dc.contributor.authorRotter, Jerome Ien
dc.contributor.authorSaleheen, Danishen
dc.contributor.authorSamani, Nilesh Jen
dc.contributor.authorSchunkert, Heriberten
dc.contributor.authorVollenweider, Peteren
dc.contributor.authorO’Rahilly, Stephenen
dc.contributor.authorDeloukas, Panosen
dc.contributor.authorDanesh, Johnen
dc.contributor.authorGoodarzi, Mark Oen
dc.contributor.authorKathiresan, Sekaren
dc.contributor.authorMeigs, James Ben
dc.contributor.authorEhm, Margaret Gen
dc.contributor.authorWareham, Nicholasen
dc.contributor.authorWaterworth, Dawn Men
dc.date.accessioned2016-06-10T16:35:47Z
dc.date.available2016-06-10T16:35:47Z
dc.date.issued2016-06-01en
dc.identifier.issn1946-6234
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/256264
dc.description.abstractRegulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
dc.description.sponsorshipNational Institutes of Health
dc.languageEnglishen
dc.language.isoenen
dc.publisherAmerican Association for the Advancement of Science
dc.titleA genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart diseaseen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via http://dx.doi.org/10.1126/scitranslmed.aad3744en
prism.number341ra76en
prism.publicationDate2016en
prism.publicationNameScience Translational Medicineen
prism.volume8en
dc.identifier.doi10.17863/CAM.205
dcterms.dateAccepted2016-05-10en
rioxxterms.versionofrecord10.1126/scitranslmed.aad3744en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-06-01en
dc.contributor.orcidSurendran, Praveen [0000-0002-4911-6077]
dc.contributor.orcidLuan, Jian'an [0000-0003-3137-6337]
dc.contributor.orcidBarroso, Ines [0000-0001-5800-4520]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.contributor.orcidEarl, Helena [0000-0003-1549-8094]
dc.contributor.orcidForouhi, Nita [0000-0002-5041-248X]
dc.contributor.orcidSharp, Stephen [0000-0003-2375-1440]
dc.contributor.orcidThompson, Deborah [0000-0003-1465-5799]
dc.contributor.orcidAbraham, Jean [0000-0003-0688-4807]
dc.contributor.orcidButterworth, Adam [0000-0002-6915-9015]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.contributor.orcidHowson, Joanna [0000-0001-7618-0050]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.contributor.orcidDanesh, John [0000-0003-1158-6791]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.identifier.eissn1946-6242
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12015/1)
pubs.funder-project-idWellcome Trust (095515/Z/11/Z)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (unknown)
pubs.funder-project-idCancer Research UK (CB4140)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (60098573)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (A15580)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (A7325)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
pubs.funder-project-idMRC (MC_UU_12015/5)
pubs.funder-project-idMRC (MC_PC_13046)
pubs.funder-project-idMRC (MR/L003120/1)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
pubs.funder-project-idEC FP7 NOE (260791)
pubs.funder-project-idEuropean Commission FP7 Network of Excellence (NoE) (260791)
pubs.funder-project-idCancer Research UK (16465)
pubs.funder-project-idAcademy of Medical Sciences (unknown)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/M008975/1)
pubs.funder-project-idAcademy of Medical Sciences (ALI 01/08/14)
pubs.funder-project-idPathological Society of Great Britain & Ireland (CDF 2012/01)
pubs.funder-project-idEuropean Commission FP7 Collaborative projects (CP) (258967)
pubs.funder-project-idCancer Research UK (C507/A16278)
pubs.funder-project-idEC FP7 CP (258967)
pubs.funder-project-idCancer Research UK (20544)
pubs.funder-project-idMRC (MR/P012442/1)
pubs.funder-project-idEuropean Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (115749)
pubs.funder-project-idEC FP7 CP (242006)
pubs.funder-project-idECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (694620)
pubs.funder-project-idCancer Research UK (A24622)
pubs.funder-project-idMRC (G0800270)
pubs.funder-project-idBritish Heart Foundation (RG/08/014/24067)
pubs.funder-project-idBritish Heart Foundation (RG/13/13/30194)
rioxxterms.freetoread.startdate2016-12-01


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