title: Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance With Clinical Outcomes.
abstract: BACKGROUND
  Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation.
  
  
  RESULTS
  Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo.
  
  
  CONCLUSIONS
  Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309.
  
  
  BACKGROUND
  ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.). jean-claude.tardif@icm-mhi.org marie-pierre.dube@umontreal.ca.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: David
authors.initials: D
authors.lastname: Rhainds
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Mathieu
authors.initials: M
authors.lastname: Brodeur
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Yassamin
authors.initials: Y
authors.lastname: Feroz Zada
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: René
authors.initials: R
authors.lastname: Fouodjio
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Sylvie
authors.initials: S
authors.lastname: Provost
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Marie
authors.initials: M
authors.lastname: Boulé
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Sonia
authors.initials: S
authors.lastname: Alem
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Jean C
authors.initials: JC
authors.lastname: Grégoire
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Philippe L
authors.initials: PL
authors.lastname: L'Allier
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Reda
authors.initials: R
authors.lastname: Ibrahim
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Guertin
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Ian
authors.initials: I
authors.lastname: Mongrain
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Anders G
authors.initials: AG
authors.lastname: Olsson
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).
authors.forename: Eric
authors.initials: E
authors.lastname: Rhéaume
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.). 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 / Q000378:metabolism; D000368:Aged; D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004952:Esters; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D013438:Sulfhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D002097:C-Reactive Protein; D002784:Cholesterol; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9
keywords: C-reactive protein; HDL; cholesterol efflux; dalcetrapib; pharmacogenetics