A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
View/ Open
Date
2016-06-01Author
Scott, RA
Freitag, DF
Li, L
Chu, AY
Surendran, P
Young, R
Grarup, N
Stancáková, A
Chen, Y
Varga, TV
Yaghootkar, H
Luan, J
Zhao, JH
Willems, SM
Wessel, J
Wang, S
Maruthur, N
Michailidou, K
Pirie, A
van der Lee, SJ
Gillson, C
Al Olama, AA
Amouyel, P
Arriola, L
Arveiler, D
Aviles-Olmos, I
Balkau, B
Barricarte, A
Barroso, I
Garcia, SB
Bis, JC
Blankenberg, S
Boehnke, M
Boeing, H
Boerwinkle, E
Borecki, IB
Bork-Jensen, J
Bowden, S
Caldas, C
Caslake, M
CVD50 consortium,
Cupples, LA
Cruchaga, C
Czajkowski, J
den Hoed, M
Dunn, JA
Earl, HM
Ehret, GB
Ferrannini, E
Ferrieres, J
Foltynie, T
Ford, I
Forouhi, NG
Gianfagna, F
Gonzalez, C
Grioni, S
Hiller, L
Jansson, J-H
Jørgensen, ME
Jukema, JW
Kaaks, R
Kee, F
Kerrison, ND
Key, TJ
Kontto, J
Kote-Jarai, Z
Kraja, AT
Kuulasmaa, K
Kuusisto, J
Linneberg, A
Liu, C
Marenne, G
Mohlke, KL
Morris, AP
Muir, K
Müller-Nurasyid, M
Munroe, PB
Navarro, C
Nielsen, SF
Nilsson, PM
Nordestgaard, BG
Packard, CJ
Palli, D
Panico, S
Peloso, GM
Perola, M
Peters, A
Poole, CJ
Quirós, JR
Rolandsson, O
Sacerdote, C
Salomaa, V
Sánchez, M-J
Sattar, N
Sharp, SJ
Sims, R
Slimani, N
Smith, JA
Thompson, DJ
Trompet, S
Tumino, R
van der A, DL
van der Schouw, YT
Virtamo, J
Walker, M
Walter, K
GERAD_EC Consortium,
Neurology Working Group of the Cohorts for Heart,
Aging Research in Genomic Epidemiology (CHARGE),
Alzheimer’s Disease Genetics Consortium,
Pancreatic Cancer Cohort Consortium,
European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD),
EPIC-InterAct,
Abraham, JE
Amundadottir, LT
Aponte, JL
Butterworth, AS
Dupuis, J
Easton, DF
Eeles, RA
Erdmann, J
Franks, PW
Frayling, TM
Hansen, T
Howson, JMM
Jørgensen, T
Kooner, J
Laakso, M
Langenberg, C
McCarthy, MI
Pankow, JS
Pedersen, O
Riboli, E
Rotter, JI
Saleheen, D
Samani, NJ
Schunkert, H
Vollenweider, P
O'Rahilly, S
CHARGE consortium,
CHD Exome+ Consortium,
CARDIOGRAM Exome Consortium,
Deloukas, P
Danesh, J
Goodarzi, MO
Kathiresan, S
Meigs, JB
Ehm, MG
Wareham, NJ
Waterworth, DM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
CVD50 consortium
GERAD_EC Consortium
Neurology Working Group of the Cohorts for Heart
Aging Research in Genomic Epidemiology (CHARGE)
Alzheimer’s Disease Genetics Consortium
Pancreatic Cancer Cohort Consortium
European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD)
EPIC-InterAct
CHARGE consortium
CHD Exome+ Consortium
CARDIOGRAM Exome Consortium
Humans
Coronary Disease
Diabetes Mellitus, Type 2
Obesity
Receptor, Cannabinoid, CB2
Receptor, Serotonin, 5-HT2C
Receptors, Somatostatin
Genotype
Alleles
Sodium-Glucose Transporter 1
Dipeptidyl Peptidase 4
Glucagon-Like Peptide-1 Receptor
Research team
Oncogenetics
Language
eng
Date accepted
2016-05-10
License start date
2016-06
Citation
Science translational medicine, 2016, 8 (341), pp. 341ra76 - ?
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Related items
Showing items related by title, author, creator and subject.
-
Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.
Zhang, YD; Hurson, AN; Zhang, H; Choudhury, PP; Easton, DF; et al. (NATURE PORTFOLIO, 2020-07-03)Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of ... -
Genetic predisposition to mosaic Y chromosome loss in blood.
Thompson, DJ; Genovese, G; Halvardson, J; Ulirsch, JC; Wright, DJ; et al. (NATURE PORTFOLIO, 2019-11-28)Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, ... -
An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk.
Wu, L; Yang, Y; Guo, X; Shu, X-O; Cai, Q; et al. (NATURE PUBLISHING GROUP, 2020-08-06)It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence ...