Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib. (April 2015)

• Record Type: Journal Article
• 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
• Is Part Of: Circulation. Volume 8:Number 2(2015)
• Publication Date: 2015-04
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000663
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>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 <italic>ADCY9</italic> gene on chromosome 16 (rs1967309; <italic>P</italic>=2.41×10<sup>–8</sup>), with 8 polymorphisms providing <italic>P</italic><10<sup>–6</sup> 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 <italic>ADCY9</italic> gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (<italic>P</italic><0.05). Marker rs2238448 in <italic>ADCY9</italic>, in linkage disequilibrium with rs1967309 (<italic>r</italic><sup>2</sup>=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (<italic>P</italic>=0.009) and events in dal-OUTCOMES (<italic>P</italic>=8.88×10<sup>–8</sup>; hazard ratio, 0.67; 95% confidence interval, 0.58–0.78).</p> </sec> <sec> <title>Conclusions—</title> <p>The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the <italic>ADCY9</italic> gene.</p> </sec> <sec> <title>Clinical Trial Information—</title> <p>URL: <ext-link ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">http://www.clinicaltrials.gov</ext-link>. Unique identifiers: NCT00658515 and NCT01059682</p> </sec> </abstract>