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Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib.
Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada.
University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland.
University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland.
University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland.
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2015 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 8, no 2, 372-382 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 8, no 2, 372-382 p.
Keyword [en]
cholesteryl ester transfer protein; dalcetrapib; high-density lipoproteins; pharmacogenetics
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:liu:diva-124059DOI: 10.1161/CIRCGENETICS.114.000663PubMedID: 25583994OAI: oai:DiVA.org:liu-124059DiVA: diva2:895623
Available from: 2016-01-19 Created: 2016-01-19 Last updated: 2016-01-29

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