@article{65305f94657f4f75b029319c50ee1319,
title = "Role of Adenylate Cyclase 9 in the Pharmacogenomic Response to Dalcetrapib: Clinical Paradigm and Molecular Mechanisms in Precision Cardiovascular Medicine",
abstract = "Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.",
keywords = "Acute coronary syndrome, Adenylate cyclase, Dalcetrapib, Macrophages, Precision medicine",
author = "David Rhainds and Packard, {Chris J.} and Brodeur, {Mathieu R.} and Niesor, {Eric J.} and Sacks, {Frank M.} and {Wouter Jukema}, J. and {Scott Wright}, R. and Waters, {David D.} and Therese Heinonen and Black, {Donald M.} and Fouzia Laghrissi-Thode and Dub{\'e}, {Marie Pierre} and Pfeffer, {Marc A.} and Tardif, {Jean Claude}",
note = "Funding Information: Dr Rhainds reports personal fees from DalCor during the conduct of the study; Dr Packard reports personal fees from Dal-Cor, personal fees from Daichi-Sankyo, grants from MesoScale Discovery, personal fees from Amgen, outside the submitted work; Dr Sacks reports personal fees from DalCor, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; in addition, Dr Sacks has a US patent on HDL (high-density lipoprotein) subspecies issued; Dr Jukema/his department has received research grants from and was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Dalcor, Daiichi San-kyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands (CVON), the Netherlands Heart Institute and the European Community Framework KP7 Programme, during the conduct of the study; Dr Waters reports personal fees from DalCor, during the conduct of the study; personal fees from Medicines Company, personal fees from Pfizer, personal fees from Resver-logix, outside the submitted work; Dr Wright reports personal fees from DalCor, outside the submitted work; Dr Black is employee of DalCor Pharmaceuticals; T. Heinonen is an employee of DalCor Pharmaceuticals; Dr Laghrissi-Thode is an employee of DalCor Pharmaceuticals; Dr Dub{\'e} reports personal fees and other from Dalcor, personal fees from Servier, personal fees from GlaxoSmithKline, outside the submitted work; in addition, Dr Dub{\'e} has a patent Methods for Treating or Preventing Cardiovascular Disorders and Lowering Risk of Cardiovascular Events licensed to Dalcor, no royalties received, a patent Genetic Markers for Predicting Responsiveness to Therapy with HDL-Raising or HDL Mimicking Agent licensed to Dalcor, no royalties received, and a patent Methods for using low dose co-chicine after myocardial infarction with royalties paid to and Invention assigned to the Montreal Heart Institute; Dr Pfeffer reports personal fees from DalCor, during the conduct of the study; personal fees from AstraZeneca, personal fees from Corvidia, personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from NovoNordisk, personal fees from PharmaScience, personal fees from Sanofi, outside the submitted work; and Dr Pfeffer receives stock options from DalCor; Dr Tardif reports grants from Amarin, grants and personal fees from Astra Zeneca, grants, personal fees and other from Dalcor, grants from Esperion, grants from Ionis, grants and personal fees from Pfizer, grants and personal fees from Sanofi, grants and personal fees from Servier, outside the submitted work; in addition, Dr Tardif has a patent Genetic markers for predicting responsiveness to therapy with HDL-raising or HDL mimicking agent pending, and a patent Methods for using low dose colchicine after myocardial infarction with royalties paid to and invention assigned to the Montreal Heart Institute. The other authors report no conflicts. Publisher Copyright: {\textcopyright} 2021 American Heart Association, Inc.",
year = "2021",
month = apr,
day = "1",
doi = "10.1161/CIRCGEN.121.003219",
language = "English (US)",
volume = "14",
pages = "E003219",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "2",
}