Abstract
From studies of rare families to genome-wide associations in populations, understanding
of human genetics has accelerated the search for new drug targets for the prevention
of atherosclerotic cardiovascular disease. DNA sequencing and genome-wide analyses
of DNA markers have illuminated rare as well as common variants in genes that regulate
lipids and ultimately atherosclerosis risk. A recent innovative approach called Mendelian
randomization can endorse specific genes and variants as causative not just for lipid
disturbances, but also for clinical cardiovascular end points. This knowledge helps
prioritize the candidate genes and proteins in the drug development pipeline. In this
review, we focus on dyslipidemia drug targets traceable to human genetic studies,
including statins and ezetimibe, as well as promising new classes such as inhibitors
of proprotein convertase subtilisin kexin 9, apolipoprotein B, microsomal triglyceride
transfer protein, cholesteryl ester transfer protein, angiopoietin-like proteins types
3 and 4 and apolipoprotein C-III. Several of these new agents have attained or are
closing in on “prime-time readiness” for clinical use in specific situations.
Résumé
Qu’il s’agisse d’études d’association pangénomique menées dans des populations ou
portant sur des caractéristiques génétiques familiales rares, la compréhension de
la génétique humaine a permis d’accélérer le développement de nouvelles cibles pharmacothérapeutiques
en vue de prévenir la maladie cardiovasculaire athérosclérotique. Le séquençage de
l’ADN et les analyses pangénomiques des marqueurs de l’ADN ont permis de mettre en
relief tant les variantes génétiques courantes que les variantes génétiques rares
de la régulation des lipides et, en fin de compte, du risque d’athérosclérose. Une
nouvelle approche innovante appelée répartition aléatoire mendélienne permet non seulement
d’associer certains gènes et leurs variantes à des perturbations lipidiques, mais
aussi à des issues cliniques cardiovasculaires. De telles données permettent de sélectionner
les gènes et les protéines qui feront l’objet de recherches pharmaceutiques. Nous
faisons un tour d’horizon des médicaments antidyslipidémiques créés à la suite de
recherches génétiques, notamment les statines et l’ézétimibe de même que de nouvelles
classes de médicaments très prometteuses comme divers inhibiteurs sélectifs, soit
les inhibiteurs de la proprotéine convertase subtilisine/kexine type 9, de l’apolipoprotéine
B, de la protéine microsomale de transfert des triglycérides, de la protéine de transfert
des esters de cholestérol, des protéines 3 et 4 de type angiopoïétine et de l’apolipoprotéine
C-III. Un grand nombre de ces agents sont désormais prêts, ou presque, pour une utilisation
clinique dans des circonstances bien précises.
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Article info
Publication history
Published online: November 10, 2016
Accepted:
November 7,
2016
Received:
September 19,
2016
Footnotes
See page 340 for disclosure information.
Identification
Copyright
© 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
