Show simple item record

dc.contributor.authorScott, RA
dc.contributor.authorFreitag, DF
dc.contributor.authorLi, L
dc.contributor.authorChu, AY
dc.contributor.authorSurendran, P
dc.contributor.authorYoung, R
dc.contributor.authorGrarup, N
dc.contributor.authorStancáková, A
dc.contributor.authorChen, Y
dc.contributor.authorVarga, TV
dc.contributor.authorYaghootkar, H
dc.contributor.authorLuan, J
dc.contributor.authorZhao, JH
dc.contributor.authorWillems, SM
dc.contributor.authorWessel, J
dc.contributor.authorWang, S
dc.contributor.authorMaruthur, N
dc.contributor.authorMichailidou, K
dc.contributor.authorPirie, A
dc.contributor.authorvan der Lee, SJ
dc.contributor.authorGillson, C
dc.contributor.authorAl Olama, AA
dc.contributor.authorAmouyel, P
dc.contributor.authorArriola, L
dc.contributor.authorArveiler, D
dc.contributor.authorAviles-Olmos, I
dc.contributor.authorBalkau, B
dc.contributor.authorBarricarte, A
dc.contributor.authorBarroso, I
dc.contributor.authorGarcia, SB
dc.contributor.authorBis, JC
dc.contributor.authorBlankenberg, S
dc.contributor.authorBoehnke, M
dc.contributor.authorBoeing, H
dc.contributor.authorBoerwinkle, E
dc.contributor.authorBorecki, IB
dc.contributor.authorBork-Jensen, J
dc.contributor.authorBowden, S
dc.contributor.authorCaldas, C
dc.contributor.authorCaslake, M
dc.contributor.authorCVD50 consortium,
dc.contributor.authorCupples, LA
dc.contributor.authorCruchaga, C
dc.contributor.authorCzajkowski, J
dc.contributor.authorden Hoed, M
dc.contributor.authorDunn, JA
dc.contributor.authorEarl, HM
dc.contributor.authorEhret, GB
dc.contributor.authorFerrannini, E
dc.contributor.authorFerrieres, J
dc.contributor.authorFoltynie, T
dc.contributor.authorFord, I
dc.contributor.authorForouhi, NG
dc.contributor.authorGianfagna, F
dc.contributor.authorGonzalez, C
dc.contributor.authorGrioni, S
dc.contributor.authorHiller, L
dc.contributor.authorJansson, J-H
dc.contributor.authorJørgensen, ME
dc.contributor.authorJukema, JW
dc.contributor.authorKaaks, R
dc.contributor.authorKee, F
dc.contributor.authorKerrison, ND
dc.contributor.authorKey, TJ
dc.contributor.authorKontto, J
dc.contributor.authorKote-Jarai, Z
dc.contributor.authorKraja, AT
dc.contributor.authorKuulasmaa, K
dc.contributor.authorKuusisto, J
dc.contributor.authorLinneberg, A
dc.contributor.authorLiu, C
dc.contributor.authorMarenne, G
dc.contributor.authorMohlke, KL
dc.contributor.authorMorris, AP
dc.contributor.authorMuir, K
dc.contributor.authorMüller-Nurasyid, M
dc.contributor.authorMunroe, PB
dc.contributor.authorNavarro, C
dc.contributor.authorNielsen, SF
dc.contributor.authorNilsson, PM
dc.contributor.authorNordestgaard, BG
dc.contributor.authorPackard, CJ
dc.contributor.authorPalli, D
dc.contributor.authorPanico, S
dc.contributor.authorPeloso, GM
dc.contributor.authorPerola, M
dc.contributor.authorPeters, A
dc.contributor.authorPoole, CJ
dc.contributor.authorQuirós, JR
dc.contributor.authorRolandsson, O
dc.contributor.authorSacerdote, C
dc.contributor.authorSalomaa, V
dc.contributor.authorSánchez, M-J
dc.contributor.authorSattar, N
dc.contributor.authorSharp, SJ
dc.contributor.authorSims, R
dc.contributor.authorSlimani, N
dc.contributor.authorSmith, JA
dc.contributor.authorThompson, DJ
dc.contributor.authorTrompet, S
dc.contributor.authorTumino, R
dc.contributor.authorvan der A, DL
dc.contributor.authorvan der Schouw, YT
dc.contributor.authorVirtamo, J
dc.contributor.authorWalker, M
dc.contributor.authorWalter, K
dc.contributor.authorGERAD_EC Consortium,
dc.contributor.authorNeurology Working Group of the Cohorts for Heart,
dc.contributor.authorAging Research in Genomic Epidemiology (CHARGE),
dc.contributor.authorAlzheimer’s Disease Genetics Consortium,
dc.contributor.authorPancreatic Cancer Cohort Consortium,
dc.contributor.authorEuropean Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD),
dc.contributor.authorEPIC-InterAct,
dc.contributor.authorAbraham, JE
dc.contributor.authorAmundadottir, LT
dc.contributor.authorAponte, JL
dc.contributor.authorButterworth, AS
dc.contributor.authorDupuis, J
dc.contributor.authorEaston, DF
dc.contributor.authorEeles, RA
dc.contributor.authorErdmann, J
dc.contributor.authorFranks, PW
dc.contributor.authorFrayling, TM
dc.contributor.authorHansen, T
dc.contributor.authorHowson, JMM
dc.contributor.authorJørgensen, T
dc.contributor.authorKooner, J
dc.contributor.authorLaakso, M
dc.contributor.authorLangenberg, C
dc.contributor.authorMcCarthy, MI
dc.contributor.authorPankow, JS
dc.contributor.authorPedersen, O
dc.contributor.authorRiboli, E
dc.contributor.authorRotter, JI
dc.contributor.authorSaleheen, D
dc.contributor.authorSamani, NJ
dc.contributor.authorSchunkert, H
dc.contributor.authorVollenweider, P
dc.contributor.authorO'Rahilly, S
dc.contributor.authorCHARGE consortium,
dc.contributor.authorCHD Exome+ Consortium,
dc.contributor.authorCARDIOGRAM Exome Consortium,
dc.contributor.authorDeloukas, P
dc.contributor.authorDanesh, J
dc.contributor.authorGoodarzi, MO
dc.contributor.authorKathiresan, S
dc.contributor.authorMeigs, JB
dc.contributor.authorEhm, MG
dc.contributor.authorWareham, NJ
dc.contributor.authorWaterworth, DM
dc.date.accessioned2018-03-01T10:04:59Z
dc.date.issued2016-06-01
dc.identifier.citationScience translational medicine, 2016, 8 (341), pp. 341ra76 - ?
dc.identifier.issn1946-6234
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1463
dc.identifier.eissn1946-6242
dc.identifier.doi10.1126/scitranslmed.aad3744
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.formatPrint
dc.format.extent341ra76 - ?
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCVD50 consortium
dc.subjectGERAD_EC Consortium
dc.subjectNeurology Working Group of the Cohorts for Heart
dc.subjectAging Research in Genomic Epidemiology (CHARGE)
dc.subjectAlzheimer’s Disease Genetics Consortium
dc.subjectPancreatic Cancer Cohort Consortium
dc.subjectEuropean Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD)
dc.subjectEPIC-InterAct
dc.subjectCHARGE consortium
dc.subjectCHD Exome+ Consortium
dc.subjectCARDIOGRAM Exome Consortium
dc.subjectHumans
dc.subjectCoronary Disease
dc.subjectDiabetes Mellitus, Type 2
dc.subjectObesity
dc.subjectReceptor, Cannabinoid, CB2
dc.subjectReceptor, Serotonin, 5-HT2C
dc.subjectReceptors, Somatostatin
dc.subjectGenotype
dc.subjectAlleles
dc.subjectSodium-Glucose Transporter 1
dc.subjectDipeptidyl Peptidase 4
dc.subjectGlucagon-Like Peptide-1 Receptor
dc.titleA genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
dc.typeJournal Article
dcterms.dateAccepted2016-05-10
rioxxterms.versionofrecord10.1126/scitranslmed.aad3744
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScience translational medicine
pubs.issue341
pubs.notesNot known
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.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.publication-statusPublished
pubs.volume8
pubs.embargo.termsNot known
icr.researchteamOncogenetics
dc.contributor.icrauthorKote-Jarai, Zsofia
dc.contributor.icrauthorEeles, Rosalind


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record