Research ArticleCardiovascular Genomics

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

Science Translational Medicine  01 Jun 2016:
Vol. 8, Issue 341, pp. 341ra76
DOI: 10.1126/scitranslmed.aad3744

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At risk by association

Genetics could soon routinely tell clinicians whether certain drugs are putting patients at risk of developing heart disease or cancer. Scott et al. looked at six genes that encode the targets of various drugs for type 2 diabetes or obesity, to see whether any genetic variations were linked to metabolic traits like body mass index and fasting glucose levels. Using several cohorts totaling more than 50,000 individuals, they landed on one particular variant in GLP1R—the gene encoding glucagon-like peptide-1 receptor, which is the target for certain glucose-lowering drugs frequently used in the clinic, like exenatide and liraglutide—associated with fasting glucose. The authors then compared this variant against disease outcomes, like coronary heart disease (CHD). In more than 200,000 individuals—some with heart disease, some as controls—the GLPR1 variant was actually protective against CHD, rather than causing any additional risk, and was not associated with various cancers or neurological diseases.

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.

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