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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

Publisher, publication year, extent ...

  • 2015
  • printrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:liu-124059
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-124059URI
  • https://doi.org/10.1161/CIRCGENETICS.114.000663DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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)
  • Lemieux Perreault, Louis-PhilippeUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Grégoire, Jean CUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Feroz Zada, YassaminUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Asselin, GéraldineUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Provost, SylvieUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Barhdadi, AminaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Rhainds, DavidUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • L'Allier, Philippe LUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Ibrahim, RedaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Upmanyu, RuchiUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Niesor, Eric JUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Benghozi, RenéeUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Suchankova, GabrielaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Laghrissi-Thode, FouziaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Guertin, Marie-ClaudeUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Olsson, Anders GUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Mongrain, IanUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Schwartz, Gregory GUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (author)
  • Dubé, Marie-PierreUniversité de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (author)
  • Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, CanadaUniversity of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland (creator_code:org_t)

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  • In:Circulation8:2, s. 372-3821942-325X1942-3268

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