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Eur J Prev Cardiol. 2017 Mar;24(5):492-504. doi: 10.1177/2047487316682186. Epub 2016 Dec 8.

Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles.

Author information

1
1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
2
2 Departments of Medicine and Genetics, Washington University School of Medicine, St Louis, USA.
3
3 Department of Public Health and Primary Care, University of Cambridge, UK.
4
4 Department of Neurology, Innsbruck Medical University, Austria.
5
5 Copenhagen University Hospital, University of Copenhagen, Denmark.
6
6 University of Glasgow, UK.
7
7 Leiden University Medical Centre, Netherlands.
8
8 University of Texas Health Science Center Houston, USA.
9
9 THL-National Institute for Health and Welfare, Helsinki, Finland.
10
10 Institute of Molecular Medicine FIMM, University of Helsinki, Finland.
11
11 Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
12
12 Department of General and Interventional Cardiology, University Heart Centre Hamburg, Germany.
13
13 University Medical Centre Hamburg Eppendorf, Hamburg, Germany.
14
14 Research Centre, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
15
15 Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.
16
16 Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Japan.
17
17 Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, USA.
18
18 The NHLBI's Framingham Heart Study, Framingham, USA.
19
19 Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, USA.
20
20 Department of Genetic Epidemiology, University of Regensburg, Germany.
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21 Department of Nephrology, University Hospital Regensburg, Germany.
22
22 Department of Life and Reproduction Sciences, University of Verona, Italy.
23
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
24 NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, UK.
25
25 Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.
26
26 Cardiology, Department of Medicine, Geneva University Hospital, Switzerland.
27
27 Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
28
28 UCB, Brussels, Belgium.
29
29 Clinical Research, Pfizer Worldwide R&D, Cambridge, USA.
30
30 Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden.
31
31 Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
32
32 Merck Research Laboratories, Cardiometabolic Disease, Kenilworth, USA.
33
33 CHDI Management/CHDI Foundation, Princeton, USA.
34
34 Department of Gene Diagnostics and Therapeutics, Research Institute, National Centre for Global Health and Medicine, Tokyo, Japan.
35
35 Department of Human Functional Genomics, Life Science Research Centre, Mie University, Japan.
36
36 UKCRC Centre of Excellence for Public Health, Queens University, Belfast, Ireland.
37
37 Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
38
38 Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
39
39 DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
40
40 Department of Medicine I, Ludwig-Maximilians-University Munich, Germany.
41
41 Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, France.
42
42 Department of Epidemiology and Public Health, EA 3430, University of Strasbourg and Strasbourg University Hospital, France.
43
43 Department of Epidemiology and Public Health, Institut Pasteur de Lille, France.
44
44 Human Genetics Center, University of Texas Health Science Center at Houston, USA.
45
45 National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh.
46
46 Centre for Global Health Research, St Michael Hospital, Toronto, Canada.
47
47 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
48
48 Deutsches Herzzentrum München, Technische Universität München, Germany.
49
49 Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, UK.
50
50 Broad Institute, Cambridge and Massachusetts General Hospital, Boston, USA.
51
51 University of Pennsylvania, Philadelphia, USA.
52
52 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
53
53 British Heart Foundation Cambridge Centre of Excellence, University of Cambridge, Cambridge, UK.
54
54 National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.

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-PLA2 enzyme 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-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results Lp-PLA2 activity 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-PLA2 activity by 65% ( p < 10-300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 activity 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-PLA2 is unlikely to be a causal risk factor.

KEYWORDS:

Human genetics; coronary heart disease; darapladib; lipoprotein-associated phospholipase A2; target validation

PMID:
27940953
PMCID:
PMC5460752
DOI:
10.1177/2047487316682186
[Indexed for MEDLINE]
Free PMC Article

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