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

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.

Figure 1. Overall study design, participating studies, and consortia

Discovery analyses were performed using targeted exome sequencing of variation in six genes tested for association with seven traits. Variants were taken forward to follow-up by targeted genotyping. Additional in silico results were obtained using available association results. Combined results were obtained by fixed-effect meta-analysis of estimates from linear or logistic regression, as appropriate. Based on the 1331 statistical tests performed in discovery analyses, p<3.8×10^-5 was used as the threshold for statistical significance. In targeted genotyping, (g) refers to studies that were directly genotyped for relevant markers, whereas (i) indicates those in which relevant variants were captured by imputation.

Figure 2. Association of GLP1R variant (rs10305492) with glycaemic traits

(A) Genetic variant association with glycaemic traits. Data are standard deviations per minor allele at rs10305492. Fasting glucose results are from the combined analysis (Table 1). Individual studies contributing to the associations for fasting insulin and 2-h glucose are in table S4. All results reflect point estimates and 95% confidence intervals (CI) from a fixed-effect meta-analysis of linear regression estimates. (B) Effect size of the GLP1R variant (in red) and loci previously reported to be associated with fasting glucose. Effect sizes are reported from discovery analyses of available MAGIC results (50), and from the combined estimate for the GLP1R variant in (A).

Figure 3. Comparison of GLP1R variant (rs10305492) associations with effects observed in clinical trials of GLP1R agonists in non-diabetic individuals and in individuals with T2D

Genetic associations are all scaled to match the effects of GLP1R-agonists on fasting glucose (i.e. per 3.3 copies of the minor (A) allele). Genetic variant results are beta estimates and 95% confidence intervals from fixed effect meta-analysis of linear regression results Trial results are estimates from fixed-effect meta-analyses of standardised mean differences between treatment and comparison groups of the individual trials listed in table S3. *Trials reported effects on body mass, whereas genetic associations were only available for BMI.

Figure 4. Association of GLP1R variant (rs10305492) with disease outcomes

Association with disease outcomes are reported per-minor allele at rs10305492. Data show odds ratios and 95% confidence intervals from logistic regression models.