Deciphering the Causal Role of sPLA2s and Lp-PLA2 in Coronary Heart Disease.
Over the last 10 to 15 years, animal and human observational studies have identified elevated levels of both proinflammatory secretory phospholipase A2-IIA and lipoprotein-associated phospholipase A2 as potential risk factors for coronary heart disease. However, Mendelian randomization, a genetic tool to test causality of a biomarker, and phase III randomized controlled trials of inhibitors of theses enzymes (varespladib and darapladib) converged to indicate that elevated levels are unlikely to be themselves causal of coronary heart disease and that inhibition had little or no clinical utility. The concordance of findings from Mendelian randomization and clinical trials suggests that for these 2 drugs, and for other novel biomarkers in future, validation of potential therapeutic targets by genetic studies (such as Mendelian randomization) before embarking on costly phase III randomized controlled trials could increase efficiency and offset the high risk of drug development, thereby facilitating discovery of new therapeutics and mitigating against the exuberant costs of drug development.
From the Center for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK (P.J.T.); and Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (M.V.H.). p.talmud@ucl.ac.uk.
Philippa J
PJ
Talmud
From the Center for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK (P.J.T.); and Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (M.V.H.).
Michael V
MV
Holmes
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000085:Acetates / Q000627:therapeutic use; D000818:Animals; D001547:Benzaldehydes / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D003327:Coronary Disease / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D007651:Keto Acids; D058990:Molecular Targeted Therapy; D010091:Oximes / Q000627:therapeutic use; D064801:Phospholipase A2 Inhibitors / Q000627:therapeutic use; D054497:Phospholipases A2, Secretory / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000085:Acetates; D001547:Benzaldehydes; D015415:Biomarkers; D007211:Indoles; D007651:Keto Acids; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; D054497:Phospholipases A2, Secretory; C117948:varespladib; C526684:PLA2G7 protein, human; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
Mendelian randomization; darapladib; secretory phospholipase-IIA; varespladib