Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib

• Published in: Circulation. Cardiovascular genetics Vol. 8; no. 2; pp. 372 - 382
• Main Authors: Tardif, Jean-Claude, Rhéaume, Eric, Lemieux Perreault, Louis-Philippe, Grégoire, Jean C., Feroz Zada, Yassamin, Asselin, Géraldine, Provost, Sylvie, Barhdadi, Amina, Rhainds, David, L’Allier, Philippe L., Ibrahim, Reda, Upmanyu, Ruchi, Niesor, Eric J., Benghozi, Renée, Suchankova, Gabriela, Laghrissi-Thode, Fouzia, Guertin, Marie-Claude, Olsson, Anders G., Mongrain, Ian, Schwartz, Gregory G., Dubé, Marie-Pierre
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.04.2015
• Subjects: Adenylyl Cyclases - genetics; Aged; Atherosclerosis - diagnostic imaging; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Carotid Intima-Media Thickness; Chromosomes, Human, Pair 16 - genetics; Female; Humans; Linkage Disequilibrium; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Sulfhydryl Compounds - administration & dosage; high-density lipoproteins; cholesteryl ester transfer protein; pharmacogenetics; dalcetrapib
• ISSN: 1942-325X; 1942-3268; 1942-3268
• DOI: 10.1161/CIRCGENETICS.114.000663

BACKGROUND—Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein 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-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10), with 8 polymorphisms providing P<10 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41–0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism 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 (r=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; hazard ratio, 0.67; 95% confidence interval, 0.58–0.78). CONCLUSIONS—The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene. CLINICAL TRIAL INFORMATION—URLhttp://www.clinicaltrials.gov. Unique identifiersNCT00658515 and NCT01059682