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Pharmacogenomic det...
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Tardif, Jean-ClaudeUniversité de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada
(author)
Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib.
- Article/chapterEnglish2015
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LIBRIS-ID:oai:DiVA.org:liu-124059
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-124059URI
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https://doi.org/10.1161/CIRCGENETICS.114.000663DOI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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.
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Rhéaume, EricUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
(author)
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Lemieux Perreault, Louis-PhilippeUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
(author)
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Grégoire, Jean CUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Feroz Zada, YassaminUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Asselin, GéraldineUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Provost, SylvieUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
(author)
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Barhdadi, AminaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Rhainds, DavidUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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L'Allier, Philippe LUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Ibrahim, RedaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Upmanyu, RuchiUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Niesor, Eric JUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Benghozi, RenéeUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Suchankova, GabrielaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Laghrissi-Thode, FouziaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Guertin, Marie-ClaudeUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Olsson, Anders GUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Mongrain, IanUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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Schwartz, Gregory GUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
(author)
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Dubé, Marie-PierreUniversité de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada
(author)
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Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, CanadaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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In:Circulation8:2, s. 372-3821942-325X1942-3268
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Provost, Sylvie
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