Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib.

Jean-Claude Tardif, Eric Rhéaume, Louis-Philippe Lemieux Perreault, Jean C Grégoire, Yassamin Feroz Zada, Géraldine Asselin, Sylvie Provost, Amina Barhdadi, David Rhainds, Philippe L L'Allier, Reda Ibrahim, Ruchi Upmanyu, Eric J Niesor, Renée Benghozi, Gabriela Suchankova, Fouzia Laghrissi-Thode, Marie-Claude Guertin, Anders G Olsson, Ian Mongrain, Gregory G Schwartz, Marie-Pierre Dubé

Journal: Circulation. Cardiovascular genetics 2016;8(2):372-82

PMID: 25583994

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Abstract

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(-8)), with 8 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 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(2)=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); 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

URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.

Address: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.). [email protected] [email protected].; Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).

DOI: 10.1161/CIRCGENETICS.114.000663

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MeSH Terms: Adenylyl Cyclases, Aged, Amides, Atherosclerosis, Carotid Intima-Media Thickness, Chromosomes, Human, Pair 16, Esters, Female, Humans, Linkage Disequilibrium, Male, Middle Aged, Pharmacogenetics, Polymorphism, Genetic, Sulfhydryl Compounds