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dc.contributor.authorScott, RAen_US
dc.contributor.authorFreitag, DFen_US
dc.contributor.authorLi, Len_US
dc.contributor.authorChu, AYen_US
dc.contributor.authorSurendran, Pen_US
dc.contributor.authorYoung, Ren_US
dc.contributor.authorGrarup, Nen_US
dc.contributor.authorStancáková, Aen_US
dc.contributor.authorChen, Yen_US
dc.contributor.authorVarga, TVen_US
dc.contributor.authorYaghootkar, Hen_US
dc.contributor.authorLuan, Jen_US
dc.contributor.authorZhao, JHen_US
dc.contributor.authorWillems, SMen_US
dc.contributor.authorWessel, Jen_US
dc.contributor.authorWang, Sen_US
dc.contributor.authorMaruthur, Nen_US
dc.contributor.authorMichailidou, Ken_US
dc.contributor.authorPirie, Aen_US
dc.contributor.authorvan der Lee, SJen_US
dc.contributor.authorGillson, Cen_US
dc.contributor.authorAl Olama, AAen_US
dc.contributor.authorAmouyel, Pen_US
dc.contributor.authorArriola, Len_US
dc.contributor.authorArveiler, Den_US
dc.contributor.authorAviles-Olmos, Ien_US
dc.contributor.authorBalkau, Ben_US
dc.contributor.authorBarricarte, Aen_US
dc.contributor.authorBarroso, Ien_US
dc.contributor.authorGarcia, SBen_US
dc.contributor.authorBis, JCen_US
dc.contributor.authorBlankenberg, Sen_US
dc.contributor.authorBoehnke, Men_US
dc.contributor.authorBoeing, Hen_US
dc.contributor.authorBoerwinkle, Een_US
dc.contributor.authorBorecki, IBen_US
dc.contributor.authorBork-Jensen, Jen_US
dc.contributor.authorBowden, Sen_US
dc.contributor.authorCaldas, Cen_US
dc.contributor.authorCaslake, Men_US
dc.contributor.authorCupples, LAen_US
dc.contributor.authorCruchaga, Cen_US
dc.contributor.authorCzajkowski, Jen_US
dc.contributor.authorden Hoed, Men_US
dc.contributor.authorDunn, JAen_US
dc.contributor.authorEarl, HMen_US
dc.contributor.authorEhret, GBen_US
dc.contributor.authorFerrannini, Een_US
dc.contributor.authorFerrieres, Jen_US
dc.contributor.authorFoltynie, Ten_US
dc.contributor.authorFord, Ien_US
dc.contributor.authorForouhi, NGen_US
dc.contributor.authorGianfagna, Fen_US
dc.contributor.authorGonzalez, Cen_US
dc.contributor.authorGrioni, Sen_US
dc.contributor.authorHiller, Len_US
dc.contributor.authorJansson, JHen_US
dc.contributor.authorJørgensen, MEen_US
dc.contributor.authorJukema, JWen_US
dc.contributor.authorKaaks, Ren_US
dc.contributor.authorKee, Fen_US
dc.contributor.authorKerrison, NDen_US
dc.contributor.authorKey, TJen_US
dc.contributor.authorKontto, Jen_US
dc.contributor.authorKote-Jarai, Zen_US
dc.contributor.authorKraja, ATen_US
dc.contributor.authorKuulasmaa, Ken_US
dc.contributor.authorKuusisto, Jen_US
dc.contributor.authorLinneberg, Aen_US
dc.contributor.authorLiu, Cen_US
dc.contributor.authorMarenne, Gen_US
dc.contributor.authorMohlke, KLen_US
dc.contributor.authorMorris, APen_US
dc.contributor.authorMuir, Ken_US
dc.contributor.authorMüller-Nurasyid, Men_US
dc.contributor.authorMunroe, PBen_US
dc.contributor.authorNavarro, Cen_US
dc.contributor.authorNielsen, SFen_US
dc.contributor.authorNilsson, PMen_US
dc.contributor.authorNordestgaard, BGen_US
dc.contributor.authorPackard, CJen_US
dc.contributor.authorPalli, Den_US
dc.contributor.authorPanico, Sen_US
dc.contributor.authorPeloso, GMen_US
dc.contributor.authorPerola, Men_US
dc.contributor.authorPeters, Aen_US
dc.contributor.authorPoole, CJen_US
dc.contributor.authorQuirós, JRen_US
dc.contributor.authorRolandsson, Oen_US
dc.contributor.authorSacerdote, Cen_US
dc.contributor.authorSalomaa, Ven_US
dc.contributor.authorSánchez, MJen_US
dc.contributor.authorSattar, Nen_US
dc.contributor.authorSharp, SJen_US
dc.contributor.authorSims, Ren_US
dc.contributor.authorSlimani, Nen_US
dc.contributor.authorSmith, JAen_US
dc.contributor.authorThompson, DJen_US
dc.contributor.authorTrompet, Sen_US
dc.contributor.authorTumino, Ren_US
dc.contributor.authorvan der A, DLen_US
dc.contributor.authorvan der Schouw, YTen_US
dc.contributor.authorVirtamo, Jen_US
dc.contributor.authorWalker, Men_US
dc.contributor.authorWalter, Ken_US
dc.contributor.authorAbraham, JEen_US
dc.contributor.authorAmundadottir, LTen_US
dc.contributor.authorAponte, JLen_US
dc.contributor.authorButterworth, ASen_US
dc.contributor.authorDupuis, Jen_US
dc.contributor.authorEaston, DFen_US
dc.contributor.authorEeles, RAen_US
dc.contributor.authorErdmann, Jen_US
dc.contributor.authorFranks, PWen_US
dc.contributor.authorFrayling, TMen_US
dc.contributor.authorHansen, Ten_US
dc.contributor.authorHowson, JMen_US
dc.contributor.authorJørgensen, Ten_US
dc.contributor.authorKooner, Jen_US
dc.contributor.authorLaakso, Men_US
dc.contributor.authorLangenberg, Cen_US
dc.contributor.authorMcCarthy, MIen_US
dc.contributor.authorPankow, JSen_US
dc.contributor.authorPedersen, Oen_US
dc.contributor.authorRiboli, Een_US
dc.contributor.authorRotter, JIen_US
dc.contributor.authorSaleheen, Den_US
dc.contributor.authorSamani, NJen_US
dc.contributor.authorSchunkert, Hen_US
dc.contributor.authorVollenweider, Pen_US
dc.contributor.authorO'Rahilly, Sen_US
dc.contributor.authorDeloukas, Pen_US
dc.contributor.authorDanesh, Jen_US
dc.contributor.authorGoodarzi, MOen_US
dc.contributor.authorKathiresan, Sen_US
dc.contributor.authorMeigs, JBen_US
dc.contributor.authorEhm, MGen_US
dc.contributor.authorWareham, NJen_US
dc.contributor.authorWaterworth, DMen_US
dc.date.accessioned2018-03-01T10:04:59Z
dc.date.issued2016-06en_US
dc.identifier.citationScience translational medicine, 2016, 8 (341), pp. 341ra76 - ?en_US
dc.identifier.issn1946-6234en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1463
dc.identifier.eissn1946-6242en_US
dc.identifier.doi10.1126/scitranslmed.aad3744en_US
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.en_US
dc.formatPrinten_US
dc.format.extent341ra76 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectCVD50 consortiumen_US
dc.subjectGERAD_EC Consortiumen_US
dc.subjectNeurology Working Group of the Cohorts for Hearten_US
dc.subjectAging Research in Genomic Epidemiology (CHARGE)en_US
dc.subjectAlzheimer’s Disease Genetics Consortiumen_US
dc.subjectPancreatic Cancer Cohort Consortiumen_US
dc.subjectEuropean Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD)en_US
dc.subjectEPIC-InterActen_US
dc.subjectCHARGE consortiumen_US
dc.subjectCHD Exome+ Consortiumen_US
dc.subjectCARDIOGRAM Exome Consortiumen_US
dc.titleA genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-05-10en_US
rioxxterms.versionofrecord10.1126/scitranslmed.aad3744en_US
rioxxterms.licenseref.startdate2016-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfScience translational medicineen_US
pubs.issue341en_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/Oncogenetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics
pubs.volume8en_US
pubs.embargo.termsNot knownen_US
icr.researchteamOncogeneticsen_US
dc.contributor.icrauthorEeles, Rosalinden_US
dc.contributor.icrauthorKote-Jarai, Zsofiaen_US


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