A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

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title = "A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease",
abstract = "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.",
author = "Scott, {Robert A.} and Freitag, {Daniel F.} and Li Li and Chu, {Audrey Y.} and Praveen Surendran and Robin Young and Niels Grarup and Alena Stanc{\'a}kov{\'a} and Yuning Chen and Varga, {Tibor V.} and Hanieh Yaghootkar and Jian'an Luan and Zhao, {Jing Hua} and Willems, {Sara M.} and Jennifer Wessel and Shuai Wang and Nisa Maruthur and Kyriaki Michailidou and Ailith Pirie and {Van Der Lee}, {Sven J.} and Christopher Gillson and {Al Olama}, {Ali Amin} and Philippe Amouyel and Larraitz Arriola and Dominique Arveiler and Iciar Aviles-Olmos and Beverley Balkau and Aurelio Barricarte and In{\^e}s Barroso and Garcia, {Sara Benlloch} and Bis, {Joshua C.} and Stefan Blankenberg and Michael Boehnke and Heiner Boeing and Eric Boerwinkle and Borecki, {Ingrid B.} and Jette Bork-Jensen and Sarah Bowden and Carlos Caldas and Muriel Caslake and Cupples, {L. Adrienne} and Carlos Cruchaga and Jacek Czajkowski and {Den Hoed}, Marcel and Dunn, {Janet A.} and Earl, {Helena M.} and Ehret, {Georg B.} and Ele Ferrannini and Jean Ferrieres and Thomas Foltynie and Ian Ford and Forouhi, {Nita G.} and Francesco Gianfagna and Carlos Gonzalez and Sara Grioni and Louise Hiller and Jansson, {Jan H{\aa}kan} and J{\o}rgensen, {Marit E.} and Jukema, {J. Wouter} and Rudolf Kaaks and Frank Kee and Kerrison, {Nicola D.} and Key, {Timothy J.} and Jukka Kontto and Zsofia Kote-Jarai and Kraja, {Aldi T.} and Kari Kuulasmaa and Johanna Kuusisto and Allan Linneberg and Chunyu Liu and Ga{\"e}lle Marenne and Mohlke, {Karen L.} and Morris, {Andrew P.} and Kenneth Muir and Martina M{\"u}ller-Nurasyid and Munroe, {Patricia B.} and Carmen Navarro and Nielsen, {Sune F.} and Nilsson, {Peter M.} and Nordestgaard, {B{\o}rge G.} and Packard, {Chris J.} and Domenico Palli and Salvatore Panico and Peloso, {Gina M.} and Markus Perola and Annette Peters and Poole, {Christopher J.} and Quir{\'o}s, {J. Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and Veikko Salomaa and S{\'a}nchez, {Mar{\'i}a Jos{\'e}} and Naveed Sattar and Sharp, {Stephen J.} and Rebecca Sims and Nadia Slimani and Smith, {Jennifer A.} and Thompson, {Deborah J.} and Stella Trompet and Rosario Tumino and {Van Der A}, {Daphne L.} and {Van Der Schouw}, {Yvonne T.} and Jarmo Virtamo and Mark Walker and Klaudia Walter and Abraham, {Jean E.} and Amundadottir, {Laufey T.} and Butterworth, {Adam S.} and Aponte, {Jennifer L.} and Jos{\'e}e Dupuis and Easton, {Douglas F.} and Eeles, {Rosalind A.} and Jeanette Erdmann and Franks, {Paul W.} and Frayling, {Timothy M.} and Torben Hansen and Howson, {Joanna M M} and Torben J{\o}rgensen and Jaspal Kooner and Markku Laakso and McCarthy, {Mark I.} and Pankow, {James S.} and Oluf Pedersen and Elio Riboli and Rotter, {Jerome I.} and Danish Saleheen and Samani, {Nilesh J.} and Heribert Schunkert and Peter Vollenweider and Stephen O'Rahilly and Panos Deloukas and John Danesh and Goodarzi, {Mark O.} and Sekar Kathiresan and Meigs, {James B.} and Ehm, {Margaret G.} and Wareham, {Nicholas J.} and Waterworth, {Dawn M.}",
year = "2016",
month = "6",
day = "1",
doi = "10.1126/scitranslmed.aad3744",
language = "English",
volume = "8",
journal = "Science Translational Medicine",
issn = "1946-6242",
publisher = "American Association for the Advancement of Science (AAAS)",
number = "341",