(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. doi:10.1126/scitranslmed.aad3744

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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.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Medicine > Warwick Medical School > Health Sciences > Clinical Trials Unit Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Non-insulin-dependent diabetes -- Treatment -- Risk factors, Drugs -- Side effects, Cardiovascular system
Journal or Publication Title:	Science Translational Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	1946-6234
Official Date:	1 June 2016
Dates:	Date Event 1 June 2016 Published
Date of first compliant deposit:	30 January 2017
Date of first compliant Open Access:	30 January 2017
Volume:	8
Number:	341
Article Number:	341ra76
DOI:	10.1126/scitranslmed.aad3744
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	GlaxoSmithKline, Medical Research Council (Great Britain) (MRC)
Grant number:	MC_UU_12015/1, R01 AG033193, UO1AG032984 (MRC)

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