title: Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics.
abstract: Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions.
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5159, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bauer
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5159, USA.
authors.forename: Sumeet A
authors.initials: SA
authors.lastname: Khetarpal
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5159, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hand
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5159, USA. Electronic address: rader@mail.med.upenn.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D006868:Hydrolysis; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D058990:Molecular Targeted Therapy; D012307:Risk Factors; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008074:Lipoproteins; D051193:Toll-Like Receptors; D014280:Triglycerides
keywords: GWAS; genetics; lipogenesis; triglycerides