title: Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib.
abstract: 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.
  
  
  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.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.). jean-claude.tardif@icm-mhi.org marie-pierre.dube@umontreal.ca.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Eric
authors.initials: E
authors.lastname: Rhéaume
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Lemieux Perreault
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Jean C
authors.initials: JC
authors.lastname: Grégoire
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Yassamin
authors.initials: Y
authors.lastname: Feroz Zada
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Géraldine
authors.initials: G
authors.lastname: Asselin
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Sylvie
authors.initials: S
authors.lastname: Provost
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Amina
authors.initials: A
authors.lastname: Barhdadi
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: David
authors.initials: D
authors.lastname: Rhainds
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Philippe L
authors.initials: PL
authors.lastname: L'Allier
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Reda
authors.initials: R
authors.lastname: Ibrahim
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Ruchi
authors.initials: R
authors.lastname: Upmanyu
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Niesor
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Renée
authors.initials: R
authors.lastname: Benghozi
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Gabriela
authors.initials: G
authors.lastname: Suchankova
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Fouzia
authors.initials: F
authors.lastname: Laghrissi-Thode
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Guertin
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Anders G
authors.initials: AG
authors.lastname: Olsson
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Ian
authors.initials: I
authors.lastname: Mongrain
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.).
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: Montreal Heart Institute (J.-C.T., E.R., L.-P.L.P., J.C.G., Y.F.Z., G.A., S.P., A.B., D.R., P.L.L'., R.I., M.-C.G., I.M., M.-P.D.), Université de Montréal (J.-C.T., E.R., J.C.G., P.L.L'., R.I., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics, Centre Montreal, Quebec, Canada (L.-P.L.P., Y.F.Z., G.A., S.P., A.B., I.M., M.-P.D.), Montreal Health Innovations Coordinating Centre (MHICC) (M.-C.G.), Montreal, Quebec, Canada; Stockholm Heart Center, Stockholm, Sweden (A.G.O.); Veterans Affairs Medical Center, University of Colorado, Denver (G.G.S.); and F. Hoffmann-La Roche, Basel, Switzerland (R.U., E.J.N., R.B., G.S., F.L.-T.). jean-claude.tardif@icm-mhi.org marie-pierre.dube@umontreal.ca.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000368:Aged; D000577:Amides; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics; D059168:Carotid Intima-Media Thickness; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004952:Esters; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013438:Sulfhydryl Compounds / Q000008:administration & dosage*
chemical_list: D000577:Amides; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9
keywords: cholesteryl ester transfer protein; dalcetrapib; high-density lipoproteins; pharmacogenetics