Dedicated to Innovation in Pharmacogenomics
The Beaulieu-Saucier Pharmacogenomics Centre (PGx Center) is a multidisciplinary centre with expertise in genomics, statistics, clinical trials and personalized medicine. The Centre, a division of the Montreal Heart Institute, leverages its expertise and state of the art facility in partnerships with industry, government and academic organizations. Importantly, it provides a broad range of genotyping and gene expression analysis capabilities that can be run in a GLP or CLIA compliant environment. Our mission is to work with our partners to discover pharmacogenomic markers or to enable their translation into clinical use.
“Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib”
The Pharmacogenomics Centre’s team had participated in a major research project in 2012 the results of which have been published on-line in January 2015 in Circulation: Cardiovascular Genetics.
Background—Dalcetrapib did not improve clinical outcomes despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting HDL as a therapeutic target. Responses to dalcetrapib may vary according to patients’ genetic profile.
Methods and Results—We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single SNP was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10-8), with eight polymorphisms providing P<10-6 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared to placebo (HR=0.61; 95%CI 0.41, 0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten SNPs in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r2=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10-8; HR=0.67, 95%CI 0.58, 0.78).
Conclusions—The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.