TY - JOUR
T1 - A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
AU - CHD Exome+ Consortium, CARDIOGRAM Exome Consortium
AU - GERAD-EC Consortium, Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
AU - Scott, Robert A.
AU - Freitag, Daniel F.
AU - Li, Li
AU - Chu, Audrey Y.
AU - Surendran, Praveen
AU - Young, Robin
AU - Grarup, Niels
AU - Stancáková, Alena
AU - Chen, Yuning
AU - Varga, Tibor V.
AU - Yaghootkar, Hanieh
AU - Luan, Jian'an
AU - Zhao, Jing Hua
AU - Willems, Sara M.
AU - Wessel, Jennifer
AU - Wang, Shuai
AU - Maruthur, Nisa
AU - Michailidou, Kyriaki
AU - Pirie, Ailith
AU - Van Der Lee, Sven J.
AU - Gillson, Christopher
AU - Al Olama, Ali Amin
AU - Amouyel, Philippe
AU - Arriola, Larraitz
AU - Arveiler, Dominique
AU - Aviles-Olmos, Iciar
AU - Balkau, Beverley
AU - Barricarte, Aurelio
AU - Barroso, Inês
AU - Garcia, Sara Benlloch
AU - Bis, Joshua C.
AU - Blankenberg, Stefan
AU - Boehnke, Michael
AU - Boeing, Heiner
AU - Boerwinkle, Eric
AU - Borecki, Ingrid B.
AU - Bork-Jensen, Jette
AU - Bowden, Sarah
AU - Caldas, Carlos
AU - Caslake, Muriel
AU - Cupples, L. Adrienne
AU - Cruchaga, Carlos
AU - Czajkowski, Jacek
AU - Den Hoed, Marcel
AU - Dunn, Janet A.
AU - Earl, Helena M.
AU - Ehret, Georg B.
AU - Ferrannini, Ele
AU - Ferrieres, Jean
AU - Schunkert, Heribert
N1 - Publisher Copyright:
Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/84973167573
U2 - 10.1126/scitranslmed.aad3744
DO - 10.1126/scitranslmed.aad3744
M3 - Article
C2 - 27252175
AN - SCOPUS:84973167573
SN - 1946-6234
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 341
M1 - 341ra76
ER -
SDG 3 Good Health and Well-being