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

Scott, Robert A.; Freitag, Daniel F.; Li, Li LU ; Chu, Audrey Y.; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning and Varga, Tibor V. LU , et al. (2016) In Science Translational Medicine 8(341).
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... (More)

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.

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Science Translational Medicine
volume
8
issue
341
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:84973167573
  • wos:000377443000003
ISSN
1946-6234
DOI
10.1126/scitranslmed.aad3744
language
English
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yes
id
5473991d-29f0-4f9e-8d92-a4018d3fbb98
date added to LUP
2016-07-12 13:03:49
date last changed
2017-11-19 04:32:10
@article{5473991d-29f0-4f9e-8d92-a4018d3fbb98,
  abstract     = {<p>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.</p>},
  articleno    = {341ra76},
  author       = {Scott, Robert A. and Freitag, Daniel F. and Li, Li and Chu, Audrey Y. and Surendran, Praveen and Young, Robin and Grarup, Niels and Stancáková, Alena and Chen, Yuning and Varga, Tibor V. and Yaghootkar, Hanieh and Luan, Jian'an and Zhao, Jing Hua and Willems, Sara M. and Wessel, Jennifer and Wang, Shuai and Maruthur, Nisa and Michailidou, Kyriaki and Pirie, Ailith and Van Der Lee, Sven J. and Gillson, Christopher and Al Olama, Ali Amin and Amouyel, Philippe and Arriola, Larraitz and Arveiler, Dominique and Aviles-Olmos, Iciar and Balkau, Beverley and Barricarte, Aurelio and Barroso, Inês and Garcia, Sara Benlloch and Bis, Joshua C. and Blankenberg, Stefan and Boehnke, Michael and Boeing, Heiner and Boerwinkle, Eric and Borecki, Ingrid B. and Bork-Jensen, Jette and Bowden, Sarah and Caldas, Carlos and Caslake, Muriel and Cupples, L. Adrienne and Cruchaga, Carlos and Czajkowski, Jacek and Den Hoed, Marcel and Dunn, Janet A. and Earl, Helena M. and Ehret, Georg B. and Ferrannini, Ele and Ferrieres, Jean and Foltynie, Thomas and Ford, Ian and Forouhi, Nita G. and Gianfagna, Francesco and Gonzalez, Carlos and Grioni, Sara and Hiller, Louise and Jansson, Jan Håkan and Jørgensen, Marit E. and Jukema, J. Wouter and Kaaks, Rudolf and Kee, Frank and Kerrison, Nicola D. and Key, Timothy J. and Kontto, Jukka and Kote-Jarai, Zsofia and Kraja, Aldi T. and Kuulasmaa, Kari and Kuusisto, Johanna and Linneberg, Allan and Liu, Chunyu and Marenne, Gaëlle and Mohlke, Karen L. and Morris, Andrew P. and Muir, Kenneth and Müller-Nurasyid, Martina and Munroe, Patricia B. and Navarro, Carmen and Nielsen, Sune F. and Nilsson, Peter M. and Nordestgaard, Børge G. and Packard, Chris J. and Palli, Domenico and Panico, Salvatore and Peloso, Gina M. and Perola, Markus and Peters, Annette and Poole, Christopher J. and Quirós, J. Ramón and Rolandsson, Olov and Sacerdote, Carlotta and Salomaa, Veikko and Sánchez, María José and Sattar, Naveed and Sharp, Stephen J. and Sims, Rebecca and Slimani, Nadia and Smith, Jennifer A. and Thompson, Deborah J. and Trompet, Stella and Tumino, Rosario and Van Der A, Daphne L. and Van Der Schouw, Yvonne T. and Virtamo, Jarmo and Walker, Mark and Walter, Klaudia and Abraham, Jean E. and Amundadottir, Laufey T. and Butterworth, Adam S. and Aponte, Jennifer L. and Dupuis, Josée and Easton, Douglas F. and Eeles, Rosalind A. and Erdmann, Jeanette and Franks, Paul W. and Frayling, Timothy M. and Hansen, Torben and Howson, Joanna M M and Jørgensen, Torben and Kooner, Jaspal and Laakso, Markku and McCarthy, Mark I. and Pankow, James S. and Pedersen, Oluf and Riboli, Elio and Rotter, Jerome I. and Saleheen, Danish and Samani, Nilesh J. and Schunkert, Heribert and Vollenweider, Peter and O'Rahilly, Stephen and Deloukas, Panos and Danesh, John and Goodarzi, Mark O. and Kathiresan, Sekar and Meigs, James B. and Ehm, Margaret G. and Wareham, Nicholas J. and Waterworth, Dawn M.},
  issn         = {1946-6234},
  language     = {eng},
  month        = {06},
  number       = {341},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease},
  url          = {http://dx.doi.org/10.1126/scitranslmed.aad3744},
  volume       = {8},
  year         = {2016},
}