%0 Journal Article %J Sci Transl Med %D 2016 %T A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. %A Scott, Robert A %A Freitag, Daniel F %A Li, Li %A Chu, Audrey Y %A Surendran, Praveen %A Young, Robin %A Grarup, Niels %A Stančáková, Alena %A Chen, Yuning %A Varga, Tibor V %A Yaghootkar, Hanieh %A Luan, Jian'an %A Zhao, Jing Hua %A Willems, Sara M %A Wessel, Jennifer %A Wang, Shuai %A Maruthur, Nisa %A Michailidou, Kyriaki %A Pirie, Ailith %A van der Lee, Sven J %A Gillson, Christopher %A Al Olama, Ali Amin %A Amouyel, Philippe %A Arriola, Larraitz %A Arveiler, Dominique %A Aviles-Olmos, Iciar %A Balkau, Beverley %A Barricarte, Aurelio %A Barroso, Inês %A Garcia, Sara Benlloch %A Bis, Joshua C %A Blankenberg, Stefan %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bowden, Sarah %A Caldas, Carlos %A Caslake, Muriel %A Cupples, L Adrienne %A Cruchaga, Carlos %A Czajkowski, Jacek %A den Hoed, Marcel %A Dunn, Janet A %A Earl, Helena M %A Ehret, Georg B %A Ferrannini, Ele %A Ferrieres, Jean %A Foltynie, Thomas %A Ford, Ian %A Forouhi, Nita G %A Gianfagna, Francesco %A Gonzalez, Carlos %A Grioni, Sara %A Hiller, Louise %A Jansson, Jan-Håkan %A Jørgensen, Marit E %A Jukema, J Wouter %A Kaaks, Rudolf %A Kee, Frank %A Kerrison, Nicola D %A Key, Timothy J %A Kontto, Jukka %A Kote-Jarai, Zsofia %A Kraja, Aldi T %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Linneberg, Allan %A Liu, Chunyu %A Marenne, Gaëlle %A Mohlke, Karen L %A Morris, Andrew P %A Muir, Kenneth %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Navarro, Carmen %A Nielsen, Sune F %A Nilsson, Peter M %A Nordestgaard, Børge G %A Packard, Chris J %A Palli, Domenico %A Panico, Salvatore %A Peloso, Gina M %A Perola, Markus %A Peters, Annette %A Poole, Christopher J %A Quirós, J Ramón %A Rolandsson, Olov %A Sacerdote, Carlotta %A Salomaa, Veikko %A Sánchez, María-José %A Sattar, Naveed %A Sharp, Stephen J %A Sims, Rebecca %A Slimani, Nadia %A Smith, Jennifer A %A Thompson, Deborah J %A Trompet, Stella %A Tumino, Rosario %A van der A, Daphne L %A van der Schouw, Yvonne T %A Virtamo, Jarmo %A Walker, Mark %A Walter, Klaudia %A Abraham, Jean E %A Amundadottir, Laufey T %A Aponte, Jennifer L %A Butterworth, Adam S %A Dupuis, Josée %A Easton, Douglas F %A Eeles, Rosalind A %A Erdmann, Jeanette %A Franks, Paul W %A Frayling, Timothy M %A Hansen, Torben %A Howson, Joanna M M %A Jørgensen, Torben %A Kooner, Jaspal %A Laakso, Markku %A Langenberg, Claudia %A McCarthy, Mark I %A Pankow, James S %A Pedersen, Oluf %A Riboli, Elio %A Rotter, Jerome I %A Saleheen, Danish %A Samani, Nilesh J %A Schunkert, Heribert %A Vollenweider, Peter %A O'Rahilly, Stephen %A Deloukas, Panos %A Danesh, John %A Goodarzi, Mark O %A Kathiresan, Sekar %A Meigs, James B %A Ehm, Margaret G %A Wareham, Nicholas J %A Waterworth, Dawn M %K Alleles %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Dipeptidyl Peptidase 4 %K Genotype %K Glucagon-Like Peptide-1 Receptor %K Humans %K Obesity %K Receptor, Cannabinoid, CB2 %K Receptor, Serotonin, 5-HT2C %K Receptors, Somatostatin %K Sodium-Glucose Transporter 1 %X

Regulatory 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.

%B Sci Transl Med %V 8 %P 341ra76 %8 2016 Jun 01 %G eng %N 341 %1 https://www.ncbi.nlm.nih.gov/pubmed/27252175?dopt=Abstract %R 10.1126/scitranslmed.aad3744 %0 Journal Article %J Nat Genet %D 2015 %T Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. %A Gaulton, Kyle J %A Ferreira, Teresa %A Lee, Yeji %A Raimondo, Anne %A Mägi, Reedik %A Reschen, Michael E %A Mahajan, Anubha %A Locke, Adam %A Rayner, N William %A Robertson, Neil %A Scott, Robert A %A Prokopenko, Inga %A Scott, Laura J %A Green, Todd %A Sparso, Thomas %A Thuillier, Dorothee %A Yengo, Loic %A Grallert, Harald %A Wahl, Simone %A Frånberg, Mattias %A Strawbridge, Rona J %A Kestler, Hans %A Chheda, Himanshu %A Eisele, Lewin %A Gustafsson, Stefan %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Qi, Lu %A Karssen, Lennart C %A van Leeuwen, Elisabeth M %A Willems, Sara M %A Li, Man %A Chen, Han %A Fuchsberger, Christian %A Kwan, Phoenix %A Ma, Clement %A Linderman, Michael %A Lu, Yingchang %A Thomsen, Soren K %A Rundle, Jana K %A Beer, Nicola L %A van de Bunt, Martijn %A Chalisey, Anil %A Kang, Hyun Min %A Voight, Benjamin F %A Abecasis, Gonçalo R %A Almgren, Peter %A Baldassarre, Damiano %A Balkau, Beverley %A Benediktsson, Rafn %A Blüher, Matthias %A Boeing, Heiner %A Bonnycastle, Lori L %A Bottinger, Erwin P %A Burtt, Noël P %A Carey, Jason %A Charpentier, Guillaume %A Chines, Peter S %A Cornelis, Marilyn C %A Couper, David J %A Crenshaw, Andrew T %A van Dam, Rob M %A Doney, Alex S F %A Dorkhan, Mozhgan %A Edkins, Sarah %A Eriksson, Johan G %A Esko, Tõnu %A Eury, Elodie %A Fadista, João %A Flannick, Jason %A Fontanillas, Pierre %A Fox, Caroline %A Franks, Paul W %A Gertow, Karl %A Gieger, Christian %A Gigante, Bruna %A Gottesman, Omri %A Grant, George B %A Grarup, Niels %A Groves, Christopher J %A Hassinen, Maija %A Have, Christian T %A Herder, Christian %A Holmen, Oddgeir L %A Hreidarsson, Astradur B %A Humphries, Steve E %A Hunter, David J %A Jackson, Anne U %A Jonsson, Anna %A Jørgensen, Marit E %A Jørgensen, Torben %A Kao, Wen-Hong L %A Kerrison, Nicola D %A Kinnunen, Leena %A Klopp, Norman %A Kong, Augustine %A Kovacs, Peter %A Kraft, Peter %A Kravic, Jasmina %A Langford, Cordelia %A Leander, Karin %A Liang, Liming %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindholm, Eero %A Linneberg, Allan %A Liu, Ching-Ti %A Lobbens, Stéphane %A Luan, Jian'an %A Lyssenko, Valeriya %A Männistö, Satu %A McLeod, Olga %A Meyer, Julia %A Mihailov, Evelin %A Mirza, Ghazala %A Mühleisen, Thomas W %A Müller-Nurasyid, Martina %A Navarro, Carmen %A Nöthen, Markus M %A Oskolkov, Nikolay N %A Owen, Katharine R %A Palli, Domenico %A Pechlivanis, Sonali %A Peltonen, Leena %A Perry, John R B %A Platou, Carl G P %A Roden, Michael %A Ruderfer, Douglas %A Rybin, Denis %A van der Schouw, Yvonne T %A Sennblad, Bengt %A Sigurðsson, Gunnar %A Stančáková, Alena %A Steinbach, Gerald %A Storm, Petter %A Strauch, Konstantin %A Stringham, Heather M %A Sun, Qi %A Thorand, Barbara %A Tikkanen, Emmi %A Tonjes, Anke %A Trakalo, Joseph %A Tremoli, Elena %A Tuomi, Tiinamaija %A Wennauer, Roman %A Wiltshire, Steven %A Wood, Andrew R %A Zeggini, Eleftheria %A Dunham, Ian %A Birney, Ewan %A Pasquali, Lorenzo %A Ferrer, Jorge %A Loos, Ruth J F %A Dupuis, Josée %A Florez, Jose C %A Eric Boerwinkle %A Pankow, James S %A van Duijn, Cornelia %A Sijbrands, Eric %A Meigs, James B %A Hu, Frank B %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Lakka, Timo A %A Rauramaa, Rainer %A Stumvoll, Michael %A Pedersen, Nancy L %A Lind, Lars %A Keinanen-Kiukaanniemi, Sirkka M %A Korpi-Hyövälti, Eeva %A Saaristo, Timo E %A Saltevo, Juha %A Kuusisto, Johanna %A Laakso, Markku %A Metspalu, Andres %A Erbel, Raimund %A Jöcke, Karl-Heinz %A Moebus, Susanne %A Ripatti, Samuli %A Salomaa, Veikko %A Ingelsson, Erik %A Boehm, Bernhard O %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Koistinen, Heikki %A Tuomilehto, Jaakko %A Hveem, Kristian %A Njølstad, Inger %A Deloukas, Panagiotis %A Donnelly, Peter J %A Frayling, Timothy M %A Hattersley, Andrew T %A de Faire, Ulf %A Hamsten, Anders %A Illig, Thomas %A Peters, Annette %A Cauchi, Stephane %A Sladek, Rob %A Froguel, Philippe %A Hansen, Torben %A Pedersen, Oluf %A Morris, Andrew D %A Palmer, Collin N A %A Kathiresan, Sekar %A Melander, Olle %A Nilsson, Peter M %A Groop, Leif C %A Barroso, Inês %A Langenberg, Claudia %A Wareham, Nicholas J %A O'Callaghan, Christopher A %A Gloyn, Anna L %A Altshuler, David %A Boehnke, Michael %A Teslovich, Tanya M %A McCarthy, Mark I %A Morris, Andrew P %K Binding Sites %K Case-Control Studies %K Chromatin Immunoprecipitation %K Chromosome Mapping %K Diabetes Mellitus, Type 2 %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Hepatocyte Nuclear Factor 3-beta %K Humans %K Islets of Langerhans %K Liver %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Receptor, Melatonin, MT2 %X

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

%B Nat Genet %V 47 %P 1415-25 %8 2015 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/26551672?dopt=Abstract %R 10.1038/ng.3437