liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
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.
Show others and affiliations
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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed
In the same journal
Circulation: Cardiovascular Genetics
Cardiac and Cardiovascular Systems

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 216 hits
ReferencesLink to record
Permanent link

Direct link