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

CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, GERAD-EC Consortium, Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), Jennifer Wessel

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Article number341ra76
JournalScience Translational Medicine
Volume8
Issue number341
DOIs
StatePublished - Jun 1 2016

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Coronary Disease
Type 2 Diabetes Mellitus
Glucose
Pharmaceutical Preparations
Genes
Exome
Cardiovascular Agents
Medical Genetics
Therapeutics
Hypoglycemic Agents
Computer Simulation
Heart Diseases
Fasting
Randomized Controlled Trials
Obesity
Alleles
Clinical Trials
Pharmacology
Safety
Glucagon-Like Peptide-1 Receptor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, GERAD-EC Consortium, Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), & Wessel, J. (2016). A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Science Translational Medicine, 8(341), [341ra76]. https://doi.org/10.1126/scitranslmed.aad3744

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. / CHD Exome+ Consortium, CARDIOGRAM Exome Consortium; GERAD-EC Consortium, Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE); Wessel, Jennifer.

In: Science Translational Medicine, Vol. 8, No. 341, 341ra76, 01.06.2016.

Research output: Contribution to journalArticle

CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, GERAD-EC Consortium, Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) & Wessel, J 2016, 'A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease', Science Translational Medicine, vol. 8, no. 341, 341ra76. https://doi.org/10.1126/scitranslmed.aad3744
CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, GERAD-EC Consortium, Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), Wessel J. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Science Translational Medicine. 2016 Jun 1;8(341). 341ra76. https://doi.org/10.1126/scitranslmed.aad3744
CHD Exome+ Consortium, CARDIOGRAM Exome Consortium ; GERAD-EC Consortium, Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) ; Wessel, Jennifer. / A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. In: Science Translational Medicine. 2016 ; Vol. 8, No. 341.
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