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

description: 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 inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 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 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 lower 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 randomised 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.