title: Genetic invalidation of Lp-PLA2as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles.
abstract: Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2(Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results Lp-PLA2activity was decreased by 64% ( p = 2.4 × 10-25) with carriage of any of the four loss-of-function variants, by 45% ( p < 10-300) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10-12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2activity by 65% ( p < 10-300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2is unlikely to be a causal risk factor.
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Gregson
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Freitag
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Praveen
authors.initials: P
authors.lastname: Surendran
authors.affiliation: 2 Departments of Medicine and Genetics, Washington University School of Medicine, St Louis, USA.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Stitziel
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Burgess
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaptoge
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Pei
authors.initials: P
authors.lastname: Gao
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Staley
authors.affiliation: 3 Department of Public Health and Primary Care, University of Cambridge, UK.|4 Department of Neurology, Innsbruck Medical University, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Willeit
authors.affiliation: 5 Copenhagen University Hospital, University of Copenhagen, Denmark.
authors.forename: Sune F
authors.initials: SF
authors.lastname: Nielsen
authors.affiliation: 6 University of Glasgow, UK.
authors.forename: Muriel
authors.initials: M
authors.lastname: Caslake
authors.affiliation: 7 Leiden University Medical Centre, Netherlands.
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.affiliation: 8 University of Texas Health Science Center Houston, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Polfus
authors.affiliation: 9 THL-National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Kuulasmaa
authors.affiliation: 9 THL-National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Kontto
authors.affiliation: 10 Institute of Molecular Medicine FIMM, University of Helsinki, Finland.|11 Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.affiliation: 12 Department of General and Interventional Cardiology, University Heart Centre Hamburg, Germany.|13 University Medical Centre Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: 14 Research Centre, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Veronesi
authors.affiliation: 14 Research Centre, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.|15 Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gianfagna
authors.affiliation: 9 THL-National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Männistö
authors.affiliation: 16 Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.affiliation: 17 Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, USA.|18 The NHLBI's Framingham Heart Study, Framingham, USA.
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: 19 Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, USA.
authors.forename: Dermot F
authors.initials: DF
authors.lastname: Reilly
authors.affiliation: 20 Department of Genetic Epidemiology, University of Regensburg, Germany.|21 Department of Nephrology, University Hospital Regensburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gorski
authors.affiliation: 22 Department of Life and Reproduction Sciences, University of Verona, Italy.
authors.forename: Vladan
authors.initials: V
authors.lastname: Mijatovic
authors.affiliation: 23 Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.|24 NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, UK.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.affiliation: 25 Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.|26 Cardiology, Department of Medicine, Geneva University Hospital, Switzerland.|27 Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.affiliation: 28 UCB, Brussels, Belgium.
authors.forename: Alex
authors.initials: A
authors.lastname: Thompson
authors.affiliation: 29 Clinical Research, Pfizer Worldwide R&D, Cambridge, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Uria-Nickelsen
authors.affiliation: 30 Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Malarstig
authors.affiliation: 31 Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: 32 Merck Research Laboratories, Cardiometabolic Disease, Kenilworth, USA.|33 CHDI Management/CHDI Foundation, Princeton, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Vogt
authors.affiliation: 16 Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Sasaoka
authors.affiliation: 34 Department of Gene Diagnostics and Therapeutics, Research Institute, National Centre for Global Health and Medicine, Tokyo, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeuchi
authors.affiliation: 34 Department of Gene Diagnostics and Therapeutics, Research Institute, National Centre for Global Health and Medicine, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
authors.affiliation: 35 Department of Human Functional Genomics, Life Science Research Centre, Mie University, Japan.
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: 36 UKCRC Centre of Excellence for Public Health, Queens University, Belfast, Ireland.
authors.forename: Frank
authors.initials: F
authors.lastname: Kee
authors.affiliation: 37 Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.|38 Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.|39 DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.|40 Department of Medicine I, Ludwig-Maximilians-University Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.affiliation: 41 Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Ferrières
authors.affiliation: 42 Department of Epidemiology and Public Health, EA 3430, University of Strasbourg and Strasbourg University Hospital, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Arveiler
authors.affiliation: 43 Department of Epidemiology and Public Health, Institut Pasteur de Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: 9 THL-National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: 44 Human Genetics Center, University of Texas Health Science Center at Houston, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Thompson
authors.affiliation: 6 University of Glasgow, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: 7 Leiden University Medical Centre, Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Wouter Jukema
authors.affiliation: 6 University of Glasgow, UK.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: 6 University of Glasgow, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Packard
authors.affiliation: 45 National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh.
authors.forename: Abdulla Al
authors.initials: AA
authors.lastname: Shafi Majumder
authors.affiliation: 46 Centre for Global Health Research, St Michael Hospital, Toronto, Canada.
authors.forename: Dewan S
authors.initials: DS
authors.lastname: Alam
authors.affiliation: 47 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: 39 DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.|48 Deutsches Herzzentrum München, Technische Universität München, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: 49 Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: 50 Broad Institute, Cambridge and Massachusetts General Hospital, Boston, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: 5 Copenhagen University Hospital, University of Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: 51 University of Pennsylvania, Philadelphia, USA.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Joanna Mm
authors.initials: JM
authors.lastname: Howson
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Di Angelantonio
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Butterworth
authors.affiliation: 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.|52 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|53 British Heart Foundation Cambridge Centre of Excellence, University of Cambridge, Cambridge, UK.|54 National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Danesh
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000187:drug effects / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D001547:Benzaldehydes / Q000627:therapeutic use*; D016022:Case-Control Studies; D003327:Coronary Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010091:Oximes / Q000627:therapeutic use*; D064801:Phospholipase A2 Inhibitors / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D012016:Reference Values; D015203:Reproducibility of Results; D018570:Risk Assessment; D016896:Treatment Outcome; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
keywords: Human genetics; coronary heart disease; darapladib; lipoprotein-associated phospholipase A2; target validation