title: CETP: Pharmacogenomics-Based Response to the CETP Inhibitor Dalcetrapib.
abstract: High-density lipoproteins are involved in reverse cholesterol transport and possess anti-inflammatory and antioxidative properties. Paradoxically, CETP (cholesteryl ester transfer protein) inhibitors have been shown to increase inflammation as revealed by a raised plasma level of high-sensitivity C-reactive protein. CETP inhibitors did not improve clinical outcomes in large-scale clinical trials of unselected patients with coronary disease. Dalcetrapib is a CETP modulator for which effects on cardiovascular outcomes were demonstrated in the dal-OUTCOMES trial to be influenced by correlated polymorphisms in theADCY9(adenylate cyclase type 9) gene (P=2.4×10-8for rs1967309). Patients with the AA genotype at rs1967309 had a relative reduction of 39% in the risk of presenting a cardiovascular event when treated with dalcetrapib compared with placebo (95% confidence interval, 0.41-0.92). In contrast, patients with the GG genotype had a 27% increase in risk, whereas heterozygotes (AG) presented a neutral result. Supporting evidence from the dal-PLAQUE-2 study using carotid ultrasonography revealed that the polymorphisms tested in theADCY9linkage disequilibrium block were associated with disease regression for patients with the protective genotype, progression for the harmful genotype, and no effect in heterozygotes (P≤0.05 and ≤0.01 for 10 and 3 polymorphisms, respectively) when comparing dalcetrapib to placebo. Strikingly concordant and significant genotype-dependent effects of dalcetrapib were also obtained for changes in high-sensitivity C-reactive protein and cholesterol efflux capacity. The Dal-GenE randomized trial is currently being conducted in patients with a recent acute coronary syndrome bearing the AA genotype at rs1967309 in theADCY9gene to confirm the effects of dalcetrapib on hard cardiovascular outcomes.
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., E.R., M.-P.D.) and Department of Medicine, Université de Montréal, Quebec, Canada (J.-C.T., E.R., M.-P.D.); and Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Quebec, Canada (M.-P.D.). 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., E.R., M.-P.D.) and Department of Medicine, Université de Montréal, Quebec, Canada (J.-C.T., E.R., M.-P.D.); and Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Quebec, Canada (M.-P.D.).
authors.forename: David
authors.initials: D
authors.lastname: Rhainds
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., E.R., M.-P.D.) and Department of Medicine, Université de Montréal, Quebec, Canada (J.-C.T., E.R., M.-P.D.); and Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Quebec, Canada (M.-P.D.).
authors.forename: Eric
authors.initials: E
authors.lastname: Rhéaume
authors.affiliation: From the Montreal Heart Institute (J.-C.T., D.R., E.R., M.-P.D.) and Department of Medicine, Université de Montréal, Quebec, Canada (J.-C.T., E.R., M.-P.D.); and Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Quebec, Canada (M.-P.D.). 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*; D000577:Amides; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D004952:Esters; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D018579:Patient Selection; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011237:Predictive Value of Tests; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9
keywords: cholesterol; coronary artery disease; genetics; inflammation; pharmacology