From lipid locus to drug target through human genomics.
Asselbergs, Folkert W
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van der Laan, S. W., Harshfield, E., Hemerich, D., Stacey, D., Wood, A., & Asselbergs, F. W. (2018). From lipid locus to drug target through human genomics.. Cardiovascular research, 114 (9), 1258-1270. https://doi.org/10.1093/cvr/cvy120
In the last decade over 175 genetic loci have robustly been associated to levels of major circulating blood lipids. Most loci are specific to one or two lipids, while some (SUGP1, ZPR1, TRIB1, HERPUD1, and FADS1) are associated to all. While exposing the polygenic architecture of circulating lipids and the underpinnings of dyslipidemia, these genome-wide association studies (GWAS) have provided further evidence of the critical role that lipids play in coronary heart disease (CHD) risk, as indicated by the 2.7-fold enrichment for macrophage gene expression in atherosclerotic plaques and the association of 25 loci (such as PCSK9, APOB, ABCG5-G8, KCNK5, LPL, HMGCR, NPC1L1, CETP, TRIB1, ABO, PMAIP1-MC4R, and LDLR) with CHD. These GWAS also confirmed known and commonly used therapeutic targets, including HMGCR (statins), PCSK9 (antibodies), and NPC1L1 (ezetimibe). As we head into the post-GWAS era, we offer suggestions for how to move forward beyond genetic risk loci, towards refining the biology behind the associations and identifying causal genes and therapeutic targets. Deep phenotyping through lipidomics and metabolomics will refine and increase the resolution to find causal and druggable targets, and studies aimed at demonstrating gene transcriptional and regulatory effects of lipid associated loci will further aid in identifying these targets. Thus, we argue the need for deeply phenotyped, large genetic association studies to reduce costs and failures and increase the efficiency of the drug discovery pipeline. We conjecture that in the next decade a paradigm shift will tip the balance towards a data-driven approach to therapeutic target development and the application of precision medicine where human genomics takes center stage.
Humans, Cardiovascular Diseases, Genetic Predisposition to Disease, Lipids, Genetic Markers, Phenotype, Dyslipidemias, Lipid Metabolism, Genetic Variation, Genome-Wide Association Study, Metabolomics, Drug Discovery, Hypolipidemic Agents, Molecular Targeted Therapy
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (116074)
WELLCOME TRUST (105602/Z/14/Z)
British Heart Foundation (RG/13/13/30194)
European Research Council (268834)
External DOI: https://doi.org/10.1093/cvr/cvy120
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278706