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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- Source :
- Science translational medicine, vol 8, iss 341
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
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.
- Subjects :
- Serotonin
Genotype
CHARGE consortium
Dipeptidyl Peptidase 4
Clinical Trials and Supportive Activities
Coronary Disease
Cardiovascular
Medical and Health Sciences
Glucagon-Like Peptide-1 Receptor
Sodium-Glucose Transporter 1
Clinical Research
Receptors
Genetics
Diabetes Mellitus
2.1 Biological and endogenous factors
Humans
Obesity
5-HT2C
Aetiology
Cannabinoid
Heart Disease - Coronary Heart Disease
Metabolic and endocrine
Alleles
Nutrition
CHD Exome+ Consortium
Human Genome
Diabetes
Alzheimer’s Disease Genetics Consortium
GERAD_EC Consortium
Neurology Working Group of the Cohorts for Heart
Biological Sciences
CB2
CARDIOGRAM Exome Consortium
CVD50 consortium
Aging Research in Genomic Epidemiology
Heart Disease
Good Health and Well Being
5.1 Pharmaceuticals
EPIC-InterAct
Development of treatments and therapeutic interventions
European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease
Somatostatin
Type 2
Pancreatic Cancer Cohort Consortium
Receptor
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Science translational medicine, vol 8, iss 341
- Accession number :
- edsair.dedup.wf.001..aece974a861f7c88962c2a8509bca1b2