Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance with Clinical Outcomes

Circulation: Cardiovascular Genetics

Volumn 9, Issue 4, 2016, Pages 340-348

  Tardif, Jean Claude ^a,b   Rhainds, David ^a   Brodeur, Mathieu ^a   Zada, Yassamin Feroz ^c   Fouodjio, René ^c   Provost, Sylvie ^a   Boulé, Marie ^a   Alem, Sonia ^a   Grégoire, Jean C ^a,b   L'Allier, Philippe L ^a,b   Ibrahim, Reda ^a,b   Guertin, Marie Claude ^c   Mongrain, Ian ^c   Olsson, Anders G ^d   Schwartz, Gregory G ^e   Rhéaume, Eric ^a,b   Dubé, Marie Pierre ^a,b,c  

^a MONTREAL HEART INSTITUTE   (Canada)

^b UNIVERSITÉ DE MONTRÉAL   (Canada)

^c Montreal Health Innovations Coordinating Center (MHICC)   (Canada)

^d LINKÖPING UNIVERSITY   (Sweden)

^e UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

Author keywords

C reactive protein; cholesterol efflux; dalcetrapib; HDL; pharmacogenetics

Indexed keywords

C REACTIVE PROTEIN; CHOLESTEROL; DALCETRAPIB; HIGH DENSITY LIPOPROTEIN; PLACEBO; ADENYLATE CYCLASE; ADENYLATE CYCLASE 9; BIOLOGICAL MARKER; CETP PROTEIN, HUMAN; CHOLESTEROL ESTER TRANSFER PROTEIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYPOCHOLESTEROLEMIC AGENT; LOW DENSITY LIPOPROTEIN CHOLESTEROL; THIOL DERIVATIVE;

ADCY9 GENE; ADULT; ANGINA PECTORIS; ARTHRALGIA; ARTICLE; ATHEROSCLEROSIS; ATRIAL FIBRILLATION; BACKACHE; BRONCHITIS; CHOLESTEROL TRANSPORT; CONTROLLED STUDY; COUGHING; DIABETES MELLITUS; DIARRHEA; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPNEA; FATIGUE; FEMALE; GASTROINTESTINAL DISEASE; GASTROINTESTINAL SYMPTOM; GENE; GENETIC ANALYSIS; GENOTYPE; HEADACHE; HUMAN; HYPERTENSION; INFLAMMATION; INFLUENZA; LIMB PAIN; MAJOR CLINICAL STUDY; MALE; MIDDLE AGED; MULTICENTER STUDY; MYALGIA; NONCARDIAC CHEST PAIN; OUTCOME ASSESSMENT; PERIPHERAL EDEMA; PHARMACOGENETICS; PHASE 3 CLINICAL TRIAL; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTOLIC BLOOD PRESSURE; THORAX PAIN; UNSTABLE ANGINA PECTORIS; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; AGED; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; CELL LINE; CLINICAL TRIAL; DRUG EFFECTS; DYSLIPIDEMIAS; ENZYMOLOGY; GENETICS; MACROPHAGE; METABOLISM; MOUSE; PHARMACOGENETIC VARIANT; TIME FACTOR; TREATMENT OUTCOME;

ADENYLYL CYCLASES; AGED; ANIMALS; ANTICHOLESTEREMIC AGENTS; ATHEROSCLEROSIS; BIOMARKERS; C-REACTIVE PROTEIN; CELL LINE; CHOLESTEROL; CHOLESTEROL ESTER TRANSFER PROTEINS; CHOLESTEROL, HDL; CHOLESTEROL, LDL; DOUBLE-BLIND METHOD; DYSLIPIDEMIAS; FEMALE; HUMANS; INFLAMMATION; MACROPHAGES; MALE; MICE; MIDDLE AGED; PHARMACOGENETICS; PHARMACOGENOMIC VARIANTS; POLYMORPHISM, SINGLE NUCLEOTIDE; SULFHYDRYL COMPOUNDS; TIME FACTORS; TREATMENT OUTCOME;

EID: 84982261588     PISSN: 1942325X     EISSN: 19423268     Source Type: Journal    
DOI: 10.1161/CIRCGENETICS.116.001405     Document Type: Article

References (32)

1. Rosenson RS, Brewer HB Jr, Ansell BJ, Barter P, Chapman MJ, Heinecke JW, Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol 2016 13 48 60. doi: 10.1038/nrcardio.2015.124
2. Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, HPS2-THRIVE Collaborative Group Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014 371 203 212. doi: 10.1056/NEJMoa1300955
3. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, AIM-HIGH Investigators Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011 365 2255 2267. doi: 10.1056/NEJMoa1107579
4. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, ILLUMINATE Investigators Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007 357 2109 2122. doi: 10.1056/NEJMoa0706628
5. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, dal-OUTCOMES Investigators Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012 367 2089 2099. doi: 10.1056/NEJMoa1206797
6. Tardif JC, Rhéaume E, Lemieux Perreault LP, Grégoire JC, Feroz Zada Y, Asselin G, Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet 2015 8 372 382. doi: 10.1161/CIRCGENETICS.114.000663
7. Lindpaintner K., Chasing-and catching-The wild goose: hypothesis-free post-hoc stratification studies as a new paradigm for drug development. Circ Cardiovasc Genet 2015 8 253 255. doi: 10.1161/CIRCGENETICS.115.001037
8. Rhainds D, Arsenault BJ, Brodeur MR, Tardif JC., An update on the clinical development of dalcetrapib (RO4607381), a cholesteryl ester transfer protein modulator that increases HDL cholesterol levels. Future Cardiol 2012 8 513 531. doi: 10.2217/fca.12.25
9. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, Determining the Efficacy and Tolerability Investigators Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010 363 2406 2415. doi: 10.1056/NEJMoa1009744
10. Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011 306 2099 2109. doi: 10.1001/jama.2011.1649
11. Nicholls SJ, Dusting GJ, Cutri B, Bao S, Drummond GR, Rye KA, Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation 2005 111 1543 1550. doi: 10.1161/01.CIR.0000159351.95399.50
12. Vaisar T, Tang C, Babenko I, Hutchins P, Wimberger J, Suffredini AF, Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity. J Lipid Res 2015 56 1519 1530. doi: 10.1194/jlr.M059089
13. Tall AR, Yvan-Charvet L., Cholesterol, inflammation and innate immunity. Nat Rev Immunol 2015 15 104 116. doi: 10.1038/nri3793
14. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011 364 127 135. doi: 10.1056/NEJMoa1001689
15. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014 371 2383 2393. doi: 10.1056/NEJMoa1409065
16. Lilly Press Release Lilly to discontinue development of evacetrapib for high-risk atherosclerotic cardiovascular disease. Eli Lilly and Company, October 12, 2015
17. Nicholls SJ, Ruotolo G, Brewer HB, Kane JP, Wang MD, Krueger KA, Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib. J Am Coll Cardiol 2015 66 2201 2210. doi: 10.1016/j.jacc.2015.09.013
18. Ray KK, Ditmarsch M, Kallend D, Niesor EJ, Suchankova G, Upmanyu R, dal-ACUTE Investigators The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial. Eur Heart J 2014 35 1792 1800. doi: 10.1093/eurheartj/ehu105
19. Yvan-Charvet L, Matsuura F, Wang N, Bamberger MJ, Nguyen T, Rinninger F, Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol 2007 27 1132 1138. doi: 10.1161/ATVBAHA.106.138347
20. Liao KP, Playford MP, Frits M, Coblyn JS, Iannaccone C, Weinblatt ME, The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc 2015 4. doi: 10.1161/JAHA.114.001588
21. Wang X, Liao D, Bharadwaj U, Li M, Yao Q, Chen C., C-reactive protein inhibits cholesterol efflux from human macrophage-derived foam cells. Arterioscler Thromb Vasc Biol 2008 28 519 526. doi: 10.1161/ATVBAHA.107.159467
22. Maitra U, Li L., Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin. Arterioscler Thromb Vasc Biol 2013 33 24 33. doi: 10.1161/ATVBAHA.112.300049
23. Cumbay MG, Watts VJ., Novel regulatory properties of human type 9 adenylate cyclase. J Pharmacol Exp Ther 2004 310 108 115. doi: 10.1124/jpet.104.065748
24. Kim SH, Ye YM, Lee HY, Sin HJ, Park HS., Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy. J Clin Pharm Ther 2011 36 399 405. doi: 10.1111/j.1365-2710.2010.01196.x
25. Pontier SM, Percherancier Y, Galandrin S, Breit A, Galés C, Bouvier M., Cholesterol-dependent separation of the beta2-adrenergic receptor from its partners determines signaling efficacy: insight into nanoscale organization of signal transduction. J Biol Chem 2008 283 24659 24672. doi: 10.1074/jbc.M800778200
26. Haidar B, Denis M, Krimbou L, Marcil M, Genest J Jr, cAMP induces ABCA1 phosphorylation activity and promotes cholesterol efflux from fibroblasts. J Lipid Res 2002 43 2087 2094
27. See RH, Caday-Malcolm RA, Singaraja RR, Zhou S, Silverston A, Huber MT, Protein kinase A site-specific phosphorylation regulates ATP-binding cassette A1 (ABCA1)-mediated phospholipid efflux. J Biol Chem 2002 277 41835 41842. doi: 10.1074/jbc.M204923200
28. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 2013 45 1238 1243. doi: 10.1038/ng.2756
29. Ward LD, Kellis M., HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 2012 40 database issue D930 D934. doi: 10.1093/nar/gkr917
30. Huang B, Zhao J, Lei Z, Shen S, Li D, Shen GX, miR-142-3p restricts cAMP production in CD4+CD25-T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep 2009 10 180 185. doi: 10.1038/embor.2008.224
31. Liu L, Das S, Losert W, Parent CA., mTORC2 regulates neutrophil chemotaxis in a cAMP-and RhoA-dependent fashion. Dev Cell 2010 19 845 857. doi: 10.1016/j.devcel.2010.11.004
32. Risøe PK, Rutkovskiy A, Ågren J, Kolseth IB, Kjeldsen SF, Valen G, Higher TNFα responses in young males compared to females are associated with attenuation of monocyte adenylyl cyclase expression. Hum Immunol 2015 76 427 430. doi: 10.1016/j.humimm.2015.03.018