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Canadian Journal of Cardiology

Genetics for the Identification of Lipid Targets Beyond PCSK9

  • Linda R. Wang
    Affiliations
    Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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  • Robert A. Hegele
    Correspondence
    Corresponding author: Dr Robert A. Hegele, Robarts Research Institute, 4288A - 1151 Richmond St North, London, Ontario N6A 5B7, Canada. Tel.: +1-519-931-5271; fax: +1-519-931-5218.
    Affiliations
    Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
    Search for articles by this author
Published:November 10, 2016DOI:https://doi.org/10.1016/j.cjca.2016.11.003

      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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