RT Journal Article
T1 A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
A1 Scott, Robert A
A1 Freitag, Daniel F
A1 Li, Li
A1 Chu, Audrey Y
A1 Surendran, Praveen
A1 Young, Robin
A1 Grarup, Niels
A1 Stancáková, Alena
A1 Chen, Yuning
A1 Varga, Tibor V
A1 Yaghootkar, Hanieh
A1 Luan, Jian'an
A1 Zhao, Jing Hua
A1 Willems, Sara M
A1 Wessel, Jennifer
A1 Wang, Shuai
A1 Maruthur, Nisa
A1 Michailidou, Kyriaki
A1 Pirie, Ailith
A1 van der Lee, Sven J
A1 Gillson, Christopher
A1 Al Olama, Ali Amin
A1 Amouyel, Philippe
A1 Arriola, Larraitz
A1 Arveiler, Dominique
A1 Aviles-Olmos, Iciar
A1 Balkau, Beverley
A1 Barricarte, Aurelio
A1 Barroso, Inês
A1 Garcia, Sara Benlloch
A1 Bis, Joshua C
A1 Blankenberg, Stefan
A1 Boehnke, Michael
A1 Boeing, Heiner
A1 Boerwinkle, Eric
A1 Borecki, Ingrid B
A1 Bork-Jensen, Jette
A1 Bowden, Sarah
A1 Caldas, Carlos
A1 Caslake, Muriel
A1 CVD50 consortium, 
A1 Cupples, L Adrienne
A1 Cruchaga, Carlos
A1 Czajkowski, Jacek
A1 den Hoed, Marcel
A1 Dunn, Janet A
A1 Earl, Helena M
A1 Ehret, Georg B
A1 Ferrannini, Ele
A1 Ferrieres, Jean
A1 Foltynie, Thomas
A1 Ford, Ian
A1 Forouhi, Nita G
A1 Gianfagna, Francesco
A1 Gonzalez, Carlos
A1 Grioni, Sara
A1 Hiller, Louise
A1 Jansson, Jan-Håkan
A1 Jørgensen, Marit E
A1 Jukema, J Wouter
A1 Kaaks, Rudolf
A1 Kee, Frank
A1 Kerrison, Nicola D
A1 Key, Timothy J
A1 Kontto, Jukka
A1 Kote-Jarai, Zsofia
A1 Kraja, Aldi T
A1 Kuulasmaa, Kari
A1 Kuusisto, Johanna
A1 Linneberg, Allan
A1 Liu, Chunyu
A1 Marenne, Gaëlle
A1 Mohlke, Karen L
A1 Morris, Andrew P
A1 Muir, Kenneth
A1 Müller-Nurasyid, Martina
A1 Munroe, Patricia B
A1 Navarro, Carmen
A1 Nielsen, Sune F
A1 Nilsson, Peter M
A1 Nordestgaard, Børge G
A1 Packard, Chris J
A1 Palli, Domenico
A1 Panico, Salvatore
A1 Peloso, Gina M
A1 Perola, Markus
A1 Peters, Annette
A1 Poole, Christopher J
A1 Quirós, J Ramón
A1 Rolandsson, Olov
A1 Sacerdote, Carlotta
A1 Salomaa, Veikko
A1 Sanchez-Perez, Maria-Jose
A1 Sattar, Naveed
A1 Sharp, Stephen J
A1 Sims, Rebecca
A1 Slimani, Nadia
A1 Smith, Jennifer A
A1 Thompson, Deborah J
A1 Trompet, Stella
A1 Tumino, Rosario
A1 van der A, Daphne L
A1 van der Schouw, Yvonne T
A1 Virtamo, Jarmo
A1 Walker, Mark
A1 Walter, Klaudia
A1 GERAD_EC Consortium, 
A1 Neurology Working Group of the Cohorts for Heart, 
A1 Aging Research in Genomic Epidemiology (CHARGE), 
A1 Alzheimer’s Disease Genetics Consortium, 
A1 Pancreatic Cancer Cohort Consortium, 
A1 European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD), 
A1 EPIC-InterAct, 
A1 Abraham, Jean E
A1 Amundadottir, Laufey T
A1 Aponte, Jennifer L
A1 Butterworth, Adam S
A1 Dupuis, Josée
A1 Easton, Douglas F
A1 Eeles, Rosalind A
A1 Erdmann, Jeanette
A1 Franks, Paul W
A1 Frayling, Timothy M
A1 Hansen, Torben
A1 Howson, Joanna M M
A1 Jørgensen, Torben
A1 Kooner, Jaspal
A1 Laakso, Markku
A1 Langenberg, Claudia
A1 McCarthy, Mark I
A1 Pankow, James S
A1 Pedersen, Oluf
A1 Riboli, Elio
A1 Rotter, Jerome I
A1 Saleheen, Danish
A1 Samani, Nilesh J
A1 Schunkert, Heribert
A1 Vollenweider, Peter
A1 O'Rahilly, Stephen
A1 CHARGE consortium, 
A1 CHD Exome+ Consortium, 
A1 CARDIOGRAM Exome Consortium, 
A1 Deloukas, Panos
A1 Danesh, John
A1 Goodarzi, Mark O
A1 Kathiresan, Sekar
A1 Meigs, James B
A1 Ehm, Margaret G
A1 Wareham, Nicholas J
A1 Waterworth, Dawn M
AB 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.
YR 2016
FD 2016
LK http://hdl.handle.net/10668/10145
UL http://hdl.handle.net/10668/10145
LA en
DS RISalud
RD Apr 8, 2025