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Pharmacogenomic det...
Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib.
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- Tardif, Jean-Claude (author)
- Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada
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- Rhéaume, Eric (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Lemieux Perreault, Louis-Philippe (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Grégoire, Jean C (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Feroz Zada, Yassamin (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Asselin, Géraldine (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Provost, Sylvie (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Barhdadi, Amina (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Rhainds, David (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- L'Allier, Philippe L (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Ibrahim, Reda (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Upmanyu, Ruchi (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Niesor, Eric J (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Benghozi, Renée (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Suchankova, Gabriela (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Laghrissi-Thode, Fouzia (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Guertin, Marie-Claude (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Olsson, Anders G (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Mongrain, Ian (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Schwartz, Gregory G (author)
- University of Colorado, Denver, USA and F. Hoffmann-La Roche, Basel, Switzerland
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- Dubé, Marie-Pierre (author)
- Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada
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Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada University of Colorado, Denver, USA and F Hoffmann-La Roche, Basel, Switzerland (creator_code:org_t)
- 2015
- 2015
- English.
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In: Circulation. - 1942-325X .- 1942-3268. ; 8:2, s. 372-382
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- cholesteryl ester transfer protein; dalcetrapib; high-density lipoproteins; pharmacogenetics
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Tardif, Jean-Cla ...
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Rhéaume, Eric
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Lemieux Perreaul ...
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Grégoire, Jean C
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Feroz Zada, Yass ...
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Asselin, Géraldi ...
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show more...
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Provost, Sylvie
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Barhdadi, Amina
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Rhainds, David
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L'Allier, Philip ...
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Ibrahim, Reda
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Upmanyu, Ruchi
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Niesor, Eric J
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Benghozi, Renée
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Suchankova, Gabr ...
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Laghrissi-Thode, ...
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Guertin, Marie-C ...
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Olsson, Anders G
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Mongrain, Ian
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Schwartz, Gregor ...
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Dubé, Marie-Pier ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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Circulation
- By the university
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Linköping University